The movie, distributed by Paramount, is the first release by Marvel Studios, which has begun financing its own productions after such studio-backed hits as the "Spider-Man," "X-Men" and "Fantastic Four" flicks.
"We could not have hoped for a better way for Marvel Studios to blast off," said David Maisel, chairman of the unit, a division of Marvel Entertainment, which stands to pull in a greater share of box office receipts and merchandising money by financing movies itself.
Debuting in second place with $15.5 million was Sony's romantic comedy "Made of Honor," starring "Grey's Anatomy" heartthrob Patrick Dempsey as a man who tries to woo his best pal after she asks him to be "maid of honor" at her wedding.
"Iron Man," which won rave reviews from many critics, features Downey as billionaire arms designer Tony Stark, a boozy womanizer who builds a high-tech suit and becomes a superhero, mending his ways after he's taken captive and sees firsthand the devastation his weapons cause.
The film is directed by Jon Favreau, and also stars Gwyneth Paltrow, Jeff Bridges and Terrence Howard.
Despite the huge "Iron Man" opening, Hollywood's overall business was down compared to the same weekend last year, when "Spider-Man 3" had a record debut of $151.1 million. The top 12 movies took in $154.1 million, off 15 percent from a year ago.
"Nonetheless, `Iron Man' did better than expected," said Paul Dergarabedian, president of box office tracker Media By Numbers. "This is certainly the shot in the arm the marketplace has needed."
Movie attendance this year is running 6 percent behind that of 2007, so the arrival of "Iron Man" may jump start the box office as the busy summer season begins.
"If that first May movie is a big hit, it tends to lead to a big summer," said Rob Moore, Paramount vice chairman. "There hadn't been a big event movie yet this year. So you have the first event movie of summer, and people go `And I hear it's really good. All right, I'm in."'
"Iron Man" was the 10th biggest opening of all time and the fourth biggest for a superhero movie. Among nonsequels, it came in behind only the first "Spider-Man," which premiered with $114.8 million.
"If we have to, we're happy to come in second to another Marvel property," Maisel said. "It emphasizes how lucky we are to have such a powerful brand that's not loved by just comic book fans but also general movie fans."
The next Marvel production arrives in June with "The Incredible Hulk," distributed by Universal and starring Edward Norton.
In limited release, David Mamet's martial-arts drama "Redbelt" opened solidly with $68,646 in six theaters. Released by Sony Pictures Classics, "Redbelt" stars Chiwetel Ejiofor as an honorable instructor caught up in corruption in the world of mixed martial-arts competitions.
Paramount Vantage's "Son of Rambow," a comic tale of two British boys making their own "Rambo" movie, also opened well with $52,549 in five theaters.
Estimated ticket sales for Friday through Sunday at U.S. and Canadian theaters, according to Media By Numbers LLC. Final figures will be released Monday.
1. "Iron Man," $100.7 million.
2. "Made of Honor," $15.5 million.
3. "Baby Mama," $10.3 million.
4. "Forgetting Sarah Marshall," $6.1 million.
5. "Harold & Kumar Escape From Guantanamo Bay," $6 million.
6. "The Forbidden Kingdom," $4.2 million.
7. "Nim's Island," $2.8 million.
8. "Prom Night," $2.5 million.
9. "21," $2.1 million.
10. "88 Minutes," $1.6 million.