"It is with terrible sadness we must report that Patrice O'Neal has passed away this morning...due to the complications of the stroke he suffered on October 19," O'Neal's agent Matt Frost said in a statement.
"Many of us have lost a close and loved friend; all of us have lost a true comic genius," Frost added.
"Yes it's true that our pal Patrice O'Neal has passed away. The funniest and best thinker I've known. PERIOD," the Sirius XM hosts said in a Twitter message.
The "Opie & Anthony" show also broke news last month that the stand-up comic, who was diabetic, had suffered a stroke last month.
Frost said O'Neal's mother Georgia was at his side when he died. O'Neal is survived by his wife, Vondecarlo, his step daughter Aymilyon and sister Zinder.
"The family wishes to thank all of the fans and friends who have expressed an outpouring of love and support for Patrice these past weeks. We ask that you please respect the family's request for privacy at this difficult time," the statement added.
O'Neal took part along with other celebrities in Comedy Central's roast of actor Charlie Sheen in September.
He also appeared in the Comedy Central special "Elephant in the Room," and had guest roles in TV shows including "The Office" and "Arrested Development".
Film appearances included "In the Cut," "25th Hour" and "Head of State."