"What a night," Romney told cheering supporters in suburban Chicago. Turning his attention past his GOP rivals, he said he had a simple message for President Barack Obama, the Democrat he hopes to face and defeat in November: "Enough. We've had enough."
Romney triumphed after benefitting from a crushing advantage in the television advertising wars, and as his chief rival struggled to overcome self-imposed political wounds in the marathon race to pick an opponent to Obama.
Returns from 47 percent of the state's precincts showed Romney gaining 50 percent of the vote compared to 33 percent for Santorum, 9 percent for Ron Paul and 7 percent for a fading Newt Gingrich.
Exit polls showed Romney preferred by primary goers who said the economy was the top issue in the campaign, and overwhelmingly favored by those who said an ability to defeat Obama was the quality they most wanted in a nominee.
The primary capped a week in which the two campaigns seemed to be moving in opposition directions - Romney increasingly focused on the general election battle against Obama while Santorum struggled to escape self-created controversies.
Most recently, he backpedaled after saying on Monday that the economy wasn't the main issue of the campaign. "Occasionally you say some things where you wish you had a do-over," he said later.
Over the weekend, he was humbled in the Puerto Rico primary after saying that to qualify for statehood the island commonwealth should adopt English as an official language.
While pre-primary polls taken several days ago in Illinois suggested a close race, Romney and Restore Our future, a super Pac that backs him, unleashed a barrage of campaign ads to erode Santorum's standing. One ad accused the former Pennsylvania senator of changing his principles while serving in Congress, while two others criticized him for voting to raise the debt limit, raise his own pay as a lawmaker and side with former Sen. Hillary Rodham Clinton to support legislation allowing felons the right to vote.
In all, Romney and Restore Our Future outspent Santorum and a super PAC that backs him by $3.5 million to $500,000, an advantage of 7-1.
Romney's victory was worth at least 13 delegates.
That gave him 535 in the overall count maintained by The Associated Press, out of 1,144 needed to win the nomination. Santorum has 253 delegates, Gingrich 135 and Paul 50.
In the long and grinding campaign, Santorum looked to rebound in next Saturday's primary in Louisiana, particularly given Romney's demonstrated difficulties winning in contests across the Deep South.
A 10-day break follows before Washington, D.C., Maryland and Wisconsin hold primaries on April 3.
Santorum is not on the ballot in the nation's capital.
Private polling shows Romney with an advantage in Maryland, and Restore Our Future launched a television ad campaign in the state during the day at a cost of more than $450,000.
Wisconsin shapes up as the next big test between Romney and Santorum, an industrial state next door to Illinois, but one where Republican politics have been roiled recently by a controversy involving a recall battle against the governor and some GOP state senators who supported legislation that was bitterly opposed by labor unions.
Already, Restore Our future has put down more than $2 million in television advertising across Wisconsin. Santorum has spent about $50,000 to answer.
Neither Newt Gingrich nor Ron Paul campaigned extensively in Illinois.
Gingrich has faded into near-irrelevance in the race, but he was defiant in a statement issued after Romney sealed his victory.
"To defeat Barack Obama, Republicans can't nominate a candidate who relies on outspending his opponents 7-1. Instead, we need a nominee who offers powerful solutions that hold the president accountable for his failures," it said.
Gingrich said his campaign will spend the time leading to the party convention "relentlessly taking the fight to President Obama."
Illinois fell into Romney's column far more easily than Michigan or Ohio had.
The night's vote count was plagued by ballot difficulties. Rupert Borgsmiller, executive director, of the Illinois State Board of Elections, said in late afternoon that 25 counties and the city of Aurora were affected by the ballot problem. He didn't know how many ballots were affected but said "clearly you can say more than hundreds."
Romney and Santorum campaigned energetically across the state, and not always in respectful tones.
"Senator Santorum has the same economic lightweight background the president has," Romney said at one point. "We're not going to replace an economic lightweight with another economic lightweight."
Santorum had a tart reply. "If Mitt Romney's an economic heavyweight, we're in trouble."
Anticipating a primary defeat, Santorum's campaign argued that the race for delegates is closer than it appears.
Santorum contends the Republican National Committee at the convention will force Florida and Arizona to allocate their delegates on a proportional basis instead of winner-take-all as the state GOP decided. Romney won both states.
On Tuesday, about four in 10 voters interviewed as they left their polling places said they were evangelical or born again. That's about half the percentage in last week's primary states of Alabama and Mississippi, where Santorum won narrowly. Despite an unusually lengthy race for the nomination, less than a third of those voting said in the polling-place survey they hoped the primary season would come to a quick end even if that meant their candidate might lose the nomination.
The findings came from preliminary results from the survey of 1,555 Illinois Republican voters, and had a margin of error of plus or minus 4 percentage points. The exit poll was conducted for The Associated Press and the television networks by Edison Research at 35 randomly selected polling places around the state.
As Illinois Republicans voted on Tuesday, Romney raised more than $1.3 million at a luncheon in Chicago.
Santorum, the former Pennsylvania senator, has been seeking to make up in broadcast interviews what he has lacked in advertising money.
On Monday, his campaign began before sun-up and ended well after dark, including four appearances at rallies around the state as well as an extraordinary 19 radio and television interviews. He accused Romney anew of putting his signature on a Massachusetts health insurance law that is similar to the one Obama pushed through Congress.
Romney cut short his planned time in Puerto Rico, site of a primary last weekend, to maximize his time in Illinois. He has eked out victories in other big industrial states over the past few weeks, beginning in Michigan on Feb. 28 and Ohio on March 6. Defeat in any would be likely to trigger fresh anxiety within the party about his ability to wrap up the nomination.
Illinois was the 28th state to hold a primary or caucus in the selection of delegates to the nominating convention, about halfway through the calendar of a Republican campaign that has remained competitive longer than most.
A change in party rules to reduce the number of winner-take-all primaries has accounted for the duration of the race. But so has Romney's difficulty in securing the support of the most conservative of the GOP political base. Santorum and Gingrich have struggled to emerge as the front-runner's sole challenger from the right.
Whatever the reasons, the race appeared unlikely to end soon, with Santorum and even Gingrich vowing to campaign into the convention.
David Espo reported from Washington