Moving back to DC, DeMatteis succeeded Gerry Conway as writer of the superhero-team title Justice League of America. When that series was cancelled in the wake of the company-wide crossover Crisis on Infinite Earths, DeMatteis stayed through its relaunch as Justice League International, scripting over the plots of Keith Giffen.
JLI took such lesser-known DC characters as Martian Manhunter, Blue Beetle, Booster Gold, Mister Miracle, Captain Atom, and Power Girl and turned the then-current preoccupation with "grim 'n' gritty" superheroes on its head. The lighthearted series emphasized the absurd aspects of people with strange powers, wearing colorful costumes, volunteering to fight evildoers. While the League had its serious side and often faced world-threatening villains, it also featured such characters as the lovably inept G'Nort, the worst Green Lantern in the Corps; Mr. Nebula, the interplanetary decorator; the Injustice League, a bunch of bumbling losers; and a flock of homicidal penguins who had been hybridized with piranhas.
In the mid-1990s, DeMatteis took over from David Michelinie as writer of The Amazing Spider-Man for a run that included the apparent death of Peter Parker's Aunt May and the beginnings of the "Clone Saga" arc. DeMatteis as well worked on such characters as Doctor Strange, Daredevil, Man-Thing, and the Silver Surfer.
DeMatteis helped launch DC's mature-audience Vertigo imprint, writing the graphic novels Mercy and Farewell, Moonshadow (a sequel to the Epic Comics series), the miniseries The Last One, and the 15-issue series Seekers Into The Mystery, the story of a Hollywood screenwriter on a journey of self-discovery and the search for universal truths.
DeMatteis contributed tales of Superman, Batman, Wonder Woman, and Doctor Fate (reinventing the character in a 1980s series penciled by Shawn McManus); redefining the Spectre, through the character of Hal Jordan, as a spirit of redemption rather than of vengeance; and in 2003, with Giffen, revived the Justice League International for the miniseries Formerly Known as the Justice League. The series won Giffen, DeMatteis and artist Kevin Maguire an Eisner Award. The team followed this with "I Can't Believe It's Not The Justice League" arc in JLA Classified and, at Marvel, a five-issue run of The Defenders. In 2006, DeMatteis and Giffen began work on two original superhero comedy series, Hero Squared and Planetary Brigade for Boom! Studios.
DeMatteis wrote an autobiographical, digest-sized miniseries Brooklyn Dreams, published by DC's Paradox Press imprint. DeMatteis' most personal work, it was later collected in one volume under the Vertigo imprint.
The Walt Disney corporation acquired Abadazad for its Hyperion Books for Children imprint. The first two books in the series — Abadazad: The Road to Inconceivable and Abadazad: The Dream Thief — were released June 2006. Hyperion announced the third book in the planned 12-book series — Abadazad: The Puppet, The Professor and The Prophet — would be released Spring 2007.
Also a musician, DeMatteis released one album in the late 1990s, How Many Lifetimes?
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