Eminem headlined Voodoo in 2000 when his career was taking off with his Grammy-winning debut album "Slim Shady."
"This is the only concert Eminem is doing all year," said Voodoo producer Steven Rehage. "We're really excited to have him back."
In 2002, Eminem won the Academy Award for a song in the film "8 Mile," in which he also played the lead. But the rapper went on hiatus after touring in 2005. It wasn't until this year that he released "Relapse," his first album since 2004.
Eminem is expected to perform songs from the new album when he opens Voodoo on Friday. Other opening day acts include Ween, The Black Keys and Fischerspooner.
On Saturday, KISS, Jane's Addiction, Wolfmother, Black Lips and George Clinton and Parliament Funkadelic are the headliners.
"It's going to be a lot of fun," said Pepper Keenan, guitarist for the heavy metal band Down, which performs Saturday. "Mardi Gras is one thing, but this city is set up for a crazy holiday like Halloween. There will be a lot of people in costume, all ghouled up. I can't wait."
In all, Voodoo will have more than 100 music acts.
New twists include hardcore punk-spoken word artist-slash-political activist Jello Biafra and K'Naan - a Somali-Canadian poet-rapper-musician - adding to the "musical gumbo," Rehage said.
There also is art to be had, including sculpture made of weather balloons and strobe lights and a 108-foot "ladder to nowhere."
"This festival is more than KISS and Eminem," Rehage said. "The art adds a quality of life, " he said.
Besides 2005, the year Hurricane Katrina devastated the city, the festival has steadily grown in attendance and in recent years has drawn more than 100,000 fans, Rehage said.
Closing acts Sunday include Lenny Kravitz, the Flaming Lips, Meat Puppets and Widespread Panic.
Widespread Panic has been active in the hurricane recovery, giving $150,000 to build a house for a Lower 9th Ward family through actor Brad Pitt's Make It Right Foundation.
John Bell, lead singer and guitarist, said the group plans to visit the neighborhood while in town for Voodoo. "It's still kind of eery because you see a lot of places where houses used to be, some of the foundations and pillars that look like grave stones. But the community is really coming together," Bell said.
Bell said New Orleans has always been one of his favorite cities to perform.
"The city itself is steeped in tradition and a huge party atmosphere," he said. "So much of the culture is based around music. It's really a gas. It's one of the best places to play."