The unnamed comedy, to air starting next year, is to star Fox as a New York City husband and father of three dealing with family and career issues and challenges, including Parkinson's disease, the network said.
Fox, 51, was diagnosed with Parkinson's, a central nervous system degenerative disorder, in 1991 and disclosed his condition publicly in 1998. He semi-retired from acting in 2000 as the symptoms of his disease worsened.
He has since become an activist for finding a cure for Parkinson's, including the 2010 creation of the Michael J. Fox Foundation for Parkinson's Research.
Since 2000 he has worked mostly as a voiceover actor in films such as "Stuart Little" and taken guest roles in TV shows including "Boston Legal," "The Good Wife" and "Curb Your Enthusiasm."
"To bring Michael J. Fox back to NBC is a supreme honor and we are thrilled that one of the great comedic television stars is coming home again," NBC Entertainment Chairman Robert Greenblatt said in a statement announcing Fox's return.
"I have no doubt that the character he will create -- and the vivid family characters surrounding him -- will be both instantly recognizable and hilarious," Greenblatt said.
Fox said he was "extremely pleased to be back at NBC with a great creative team and a great show."
Fox starred as young Republican Alex P. Keaton in the NBC sitcom "Family Ties" from 1982 to 1989, winning three Emmy Awards and a Golden Globe Award.
He starred as Deputy New York Mayor Mike Flaherty in the ABC sitcom "Spin City" starting in 1996, but left the show in 2000 -- replaced by Heather Locklear in the 1999-2000 season. Fox won an Emmy, three Golden Globes and two Screen Actors Guild Awards for his "Spin City" work.
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