The blaze broke out at 4:00 a.m. Friday at the Salem Village Apartments in the 500 block of Oakdale Road.
Firefighters arrived to find heavy flames coming from the building and a second alarm was later struck.
The fire appears to have started in a rear apartment on the ground floor. The residents who lived there suffered serious injuries.
Family members have identified the victims as 64-year-old Sam Watts and Joseph Yarusso, who is in his early 70s.
Fire officials say another resident suffered minor smoke inhalation and a firefighter also suffered minor injuries.
Loud persistent smoke alarms woke residents and sent them rushing into the freezing morning as flames lit up the sky.
Kelley Cram and her teenage sons made it out. She said the smoke in the hallways was blinding.
"You couldn't see anything. You couldn't see the stairs, you couldn't see anything past the smoke. I came out past the apartment below me and it was on fire. I assume it was the gentleman that lives there who was sitting on the sidewalk, he was coughing a lot I hope he is all right," said Cram.
Babajide Ayodeji helped his wife and children get out through the thick smoke.
"Flames through the hallway and behind the third floor was heavy fire and thick smoke," said Ayodeji.
Flames poured out of the 12 unit apartment block and it took about an hour for crews to bring the blaze under control.
The Red Cross is providing help for 59 people. Officials expect that the landlord will relocate most people to nearby vacant apartments.
However the fire victims' belongings are left in boarded up apartments and are damaged or destroyed.
"We are giving them what's called 'client assistance cards' for food, groceries, bedding, and linens since they won't have anything to sleep on," said Joe Miller, American Red Cross.
Fire investigators believe they know where the fire started, but they are not yet sure how.
"We're looking somewhere in a bottom floor apartment here. At this point our investigation is still ongoing," said Robert Fox, Chief Deputy State Fire Marshal.
Officials say there is no indication that the fire in suspicious.