Last year it was Alicia Keys who headlined his inaugural Hope Rising! show in Toronto, and this year Annie Lennox, Sarah McLachlan and Angelique Kidjo joined him to raise money for community-based organizations providing AIDS relief in Africa.
During a press conference in the hours before the show, McLachlan and Kidjo jokingly fought over who was more "madly in love" with Lewis and his tireless work with his namesake foundation.
Lewis returned the favour by pointing out that those who participate in his charity events are kindred spirits.
"The factor that drives us is selflessness. You cannot imagine how many celebrities, forgive me, are prima donnas and martinets and you don't want to spend a whole lot of time with them," he said.
"But you have this wonderful handful of performers and celebrities in the world who give of themselves because they believe deeply in the issues and it means everything to them. And that underlies our choice this year and last year and what our choices will be in the future — people who are so genuine about the causes rather than self aggrandizing."
This year's event focuses on the plight of women in Africa who are living with AIDS, Lewis said.
"The group that has been least well-responded to in the entire pandemic are women, curiously enough, even though they represent 50 per cent of the infections worldwide and 60 per cent of the infections in Africa," he said.
"There has been a lack of urgency and intervention to deal with stigma, to deal with discrimination, to deal with the cultural reality of an absence of sexual autonomy and independence, of all the things that besiege the lives of women in the high-prevalence countries —those things have largely been overlooked in the international community."
Still, as the name of the event suggests, Lewis is optimistic.
"Of course there are serious glimmers of light," he said, pointing to how both U.S. President Barack Obama and secretary of state Hillary Clinton have talked of "an AIDS-free generation."
"To be able to talk about that prospect, although it is much further off than people are ready to acknowledge, suggests that we are making some progress."
McLachlan said she planned to perform a new song at the concert, which tied in with the night's theme of rallying around women — both those struggling with the disease and those who offer support in times of crisis.
"This song is sort of indicative of that, the power and the struggle that we will do anything as women, as mothers," she said.
"I think it's profoundly important for all of us to recognize that we are all in this together as human beings, we're all living in this very small planet."