The four-day festival in the western town of Angouleme attracted 200,000 people last year.
This year's guests — including some of the biggest names in comics and graphic novels from around the world — will find themselves under unprecedented surveillance after the attacks on satirical magazine Charlie Hebdo in Paris on January 7 that left 12 dead.
"The 2015 festival will be a time for remembering but we also want to show that life goes on," said festival director Franck Bondoux.
Graphic novel writers, press cartoonists and animators will be among the stars in attendance, which this year features special displays on Asian cartoons and Jack Kirby, creator of "Captain America", "Hulk" or "X-Men".
But three weeks on from the attacks in Paris, it is "the spirit of Charlie" that will weigh heaviest on this 42nd edition of the festival.
A number of special commemorations are planned, including a one-off Grand Prix honouring the history of the magazine and the inauguration of a new "Charlie Award for Freedom of Expression".
The prize will this year go to the cartoonists killed in the attack, and in future will be awarded to artists fighting for free speech around the world.
The festival organisers have also collected over a thousand contributions from artists around the world in homage to Charlie Hebdo.
And past front pages from the magazine will be plastered all over the town in the style of an electoral campaign.
Comic books are hugely popular in France, with 35 million sold in the country last year.
Three renowned cartoonists are in the running for the lifetime achievement award on Sunday night, the Grand Prix d'Angouleme.
They are Japan's Katsuhiro Otomo, creator of the cult manga series Akira; Britain's Alan Moore, who wrote "Watchmen" and "V is for Vendetta"; and Belgian Hermann Huppen, known for a wide range of styles from westerns to historical fiction.
Otomo would be the first manga cartoonist to win the coveted award, which last year went to "Calvin and Hobbes" creator Bill Watterson.
The festival climaxes with the prize for best album, with 35 comic books in the running.
Among the other stars in attendance will be godfather of manga Jiro Taniguchi, presenting a retrospective in Europe for the first time.