The month-long trek will be headlined by Megadeth, with Lamb Of God, Opeth, Arch Enemy, Overkill, Into Eternity, Sanctity, and The Smashup also confirmed to appear.
Dates run from September 7 to October 8, starting in San Diego and finishing in Sunrise, Fla. A number of cities and venues are still TBA, but organizers say Gigantour will hit outdoor venues in 25 major markets.
"This is the concert that I, as a heavy metal music fan, would want to see," Mustaine said. "It is going to be something to look forward to each year, to see what kind of tremendous talent we can assemble for Gigantour festivals in the years to come."
More acts will be added to the two-stage festival in the coming weeks. The trek is sponsored by Xbox 360's upcoming game "Gears Of War."
Last year's inaugural Gigantour featured Megadeth, Dream Theater, Fear Factory, Anthrax and many more. A double-disc live album from the 2005 tour is due for release August 22, with a two-DVD edition out September 5.