Diddy's REVOLT company confirmed the death Saturday but no other details were immediately available. Harrell was the vice chairman at REVOLT.
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"We can confirm the passing of Andre Harrell," Roma Khanna, the CEO of REVOLT Media & TV, said in a statement. "Everyone in the REVOLT family is devastated by the loss of our friend, mentor and Vice Chairman. Andre's impact on Hip Hop, the culture and on all of us personally has been immeasurable and profound. May he Rest In Peace."
Harrell launched his New York City-based label in 1986, eventually dominating the urban music scene with multiple hit songs and platinum-selling albums.
He first found success in the late '80s with debut albums from Heavy D & the Boyz, Al B. Sure! and Guy, the R&B trio that also included megaproducer Teddy Riley, the leader of the New Jack Swing movement.
In 1990, Diddy enters Harrell's office. He received an internship at Uptown and quickly rose the ranks after finding success with just-signed acts including R&B group Jodeci and Blige, who was dubbed the Queen of Hip-Hop Soul with the release of her 1992 debut, "What's the 411?" Uptown also released Notorious B.I.G.'s first single, 1993's "Party and Bull----," which was featured on a film soundtrack.
Diddy often credits Harrell with giving him the tools to find success in music and life, even saying Harrell was like a father figure to him.
"Andre Harrell influenced me the most and I don't know if that will ever change," Diddy said in an interview with HipHollywood.
In 1993, though, Harrell let Diddy go from Uptown. Harrell said one of the reasons he fired Diddy was because MCA Records - the label's distributor - didn't want to release B.I.G.'s debut album because of its raw and rough subject matter about street life.
"I didn't want to sit there and be the one confining Puff because the corporation was telling me to do that. I'm not built that way," Harrell said in an interview with Wall Street Journal in 2014. "I told Puff he needs to go and create his own opportunity: 'You're red-hot right now. I'm really letting you go so you can get rich.'"
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Diddy quickly launched Bad Boy Records, taking B.I.G. with him and releasing his classic album "Ready to Die" in 1994.
"And Biggie Smalls ended up becoming my favorite rapper," Harrell told WSJ.
Harrell was born in the Harlem borough of New York on Sept. 26, 1960. He was part of the rap duo Dr. Jeckyll & Mr. Hyde, releasing several songs before dropping their debut album, "The Champagne of Rap," in 1985.
Harrell began working for Russell Simmons at Def Jam in the '80s, quickly becoming an executive and helping build the careers for acts such as Run-DMC and LL Cool J.
"So many can say they are successful because Andre Harrell gave them their start. He was so beloved because he made his living uplifting others," Simmons posted Saturday on Instagram. "We celebrate him in his passing because we were so blessed for his presence... He gave everything he had. God makes the best plans R.I.P @andreharrell."
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Harrell left to launch Uptown, where he also had success with Soul for Real, Lost Boyz, Christopher Williams, Monifah and Father MC. Harrell's talent even extended to television and movies. He executive produced the hit '90s police TV drama "New York Undercover," which ran for four seasons. He also produced the 1992 Halle Berry comedy "Strictly Business" and 2003's "Honey," starring Jessica Alba.
Several members of the entertainment community mourned Harrell's death on social media, including Swizz Beatz, Erykah Badu, L.A. Reid, D-Nice and Lena Waithe. Usher called Harrell a "KING" in his post.
"My heart is breaking and I can't stop crying. He was an amazing friend and I will miss him forever," Mariah Carey tweeted.
Questlove of The Roots wrote an emotional post, calling Harrell's death "a staggering loss."
"He gave you the best soundtracks of your life man and you didn't even know it. We never gave him his flowers," he continued. "He redefined the party!"
Harrell became president and CEO of Motown Records from 1995 to 1997.
BET announced it was producing a three-part television series about Harrell and Uptown Records. It will premiere sometime this year.