Now at 80, and taking 25 pills a day for his failing health, Lewis is approaching his curtain calls dogged by activists who contend that the show is designed to evoke pity rather than empower the disabled.
Led by a former muscular dystrophy poster boy from Chicago, the activists scored what they call their "big triumph" last November as protesters in wheelchairs ambushed Lewis in an appearance at the Harold Washington Library Center in Chicago.
As they interrupted his speech, Lewis reacted as he has for years to critics - denouncing them and then storming off the stage.
"They want me to stop the telethon because I make them look pitiful," Lewis said, according to a recording made by an audience member. "What is more pitiful than this?"
The 21-hour telethon - scheduled to air on 190 stations nationwide starting tonight, including on the Fox affiliate WBN in Baltimore - moves to Las Vegas after a 12-year run in Hollywood. As they have for most Labor Days in the past 15 years, protesters plan to appear at several satellite telethon locations around the country to denounce "the charity mentality."
"Jerry Lewis has got to go," said Mike Ervin, 50, a freelance writer and disability rights proponent. He has mockingly formed a group in Chicago called "Jerry's Orphans" that plays off Lewis calling show participants "Jerry's Kids."
Ervin is distributing a documentary, The Kids Are All Right, which chronicles his years of dissent.
Despite the protesters' urgings, the telethon has not changed its ways and has not promoted accessibility for the disabled, better housing and employment possibilities, activists say.
"The concerns don't seem to sink in," said Andy Imparato, president of the American Association of People with Disabilities.
In an interview last week at the South Coast hotel-casino, Lewis said he has no intention of making peace with his detractors. "Oh God, why should I?" he asked.
Supporters say Lewis has been unfairly targeted.
"He is worthy of a major, major pat on the back for a job well done," said Steve Mikita, an assistant Utah attorney general who has a form of the disease.
Known as the "King of Comedy," Lewis is more than a public face for muscular dystrophy fundraising. He is its driving force. How Lewis became linked with muscular dystrophy - the more common strain affects 200,000 Americans - remains a mystery. Lewis refuses to discuss it.
"It was personal, private," he told reporters last week.
Muscular dystrophy is a catchall term for more than 30 genetic diseases that weaken and degenerate muscles. In all, about 1 million Americans are affected - the worst cases often being boys who grow unable to walk or breathe without a respirator.
Lewis' goal has been to fund research to find a cure; he has raised $1.35 billion. While a cure remains elusive, telethon funds spearheaded research that identified the gene and protein defining the disease and ultimately helped lengthen life. Charity watchdog groups give the Muscular Dystrophy Association high marks.
Through four decades, Lewis has never missed a telethon, even while suffering from an addiction to painkillers. In recent years, a steroid used to treat pulmonary fibrosis, a chronic lung ailment, ballooned his weight.
Never one for political correctness, Lewis has been prone to faux pas on the telethon.
But in 1990, Lewis went too far, disabled-rights activists said. In a Parade Magazine article, Lewis envisioned himself sitting in a wheelchair, with muscular dystrophy.
"I realize my life is half, so I must learn to do things halfway," he wrote. "I just have to learn to try to be good at being a half a person."
Coming as the disabled movement was blossoming, Lewis became the bull's-eye for activists. Ervin and his sister Cris Matthews - who had appeared as muscular dystrophy kids on a local television fundraiser in 1961 - led the protest.
"The telethon gives a negative message about people with disabilities," said Laura Hershey, once a "Jerry's Kid" who organized a movement in Denver called "Tune Jerry Out."
Lewis said that in hindsight his Parade piece "would be different today." Still, he refers to the activists as a small band of inconsequential troublemakers.
"I paid for their wheelchairs," he said, speaking metaphorically about his work.
E.A. Torriero writes for the Chicago Tribune.