The Warner/New Line romcom opened significantly better than expected, grossing an estimated $27.5m from 3,175 screens, for a per-screen average of $8,649.
With Jennifer Aniston, Drew Barrymore, Ben Affleck, Scarlett Johansson and Jennifer Connelly heading an ensemble cast for director Ken Kwapis, the film, based on a popular self-help book, got mixed reviews but drew a sizeable, 80% female audience.
The performance was another triumph for Aniston, who last appeared in Christmas hit Marley and Me, and for New Line, which, since it was absorbed by parent Warner, has delivered hits including Sex and the City and Four Christmases.
It also helped maintain Hollywood's hot box office streak: between them this weekend's top ten films grossed nearly 49% more than the top ten from the corresponding weekend last year.
Last weekend's box office leader, Fox-distributed EuropaCorp thriller Taken, was down only 17.9% this weekend, taking second place on the chart with an estimated $20.3m from 3,184 screens (average - $6,376).
In third place was new release Coraline, which also beat expectations with an estimated $16.3m from 2,299 screens (average - $7,105).
The 3D stop-motion animated adventure from director Henry Selick (The Nightmare Before Christmas) and production companies Pandemonium and Laika capitalised on strong reviews and familiarity with the Neil Gaiman book on which it is based.
Distributor Focus Features said the opening was the second biggest ever for a stop-motion animated film, behind only the June 2000 debut of DreamWorks' Chicken Run.
The Pink Panther 2, from MGM and Columbia, opened in fourth place, but performed below expectations with an estimated $12m from 3,243 screens (average - $3,700).
With Steve Martin back as Inspector Clouseau, the family comedy sequel, which was slammed by critics, had been expected to get closer to the $20.2m opening of its predecessor, the 2005 remake of the original 1964 Pink Panther, which eventually earned $82.2m domestically.
In fifth place, Sony's Paul Blart: Mall Cop continued its surprisingly strong run, dropping only 20.7% in its fourth week to an estimated $11m from 3,169 screens (average - $3,471).
The weekend's fourth new release, paranormal thriller Push, ranked sixth, with an estimated $10.2m from 2,313 screens (average - $4,410). The Summit release, produced with Icon Entertainment, stars Chris Evans and Dakota Fanning (who also voices the title character in Coraline) and is directed by Paul McGuigan.
Next week's wide releases are: Buena Vista's romantic comedy Confessions of a Shopaholic, with Isla Fisher starring for director P J Hogan; Warner/New Line's re-imagining of eighties chiller Friday the 13th, from director Marcus Nispel; and Sony's thriller The International, with Tom Tykwer directing Clive Owen and Naomi Watts.
Estimated Top 10 North America Feb 6-8, 2009
Film (Dist)/Int'l dist/Est wkd gross/Est total to date
1 (-) He's Just Not That Into You (Warner Bros) NLI $27.5m -
2 (1) Taken (Fox) EuropaCorp $20.3m $53.4m
3 (-) Coraline (Focus) UPI $16.3m -
4 (-) The Pink Panther 2 (Sony) SPRI $12m -
5 (2) Paul Blart: Mall Cop (Sony) SPRI $11m $97m
6 (-) Push (Summit) Summit/Icon $10.2m -
7 (6) Slumdog Millionaire (Fox Searchlight) Pathe Int'l $7.4m $77.4m
8 (5) Gran Torino (Warner Bros) WBPI/Village Roadshow $7.2m $120.3m
9 (3) The Uninvited (DreamWorks-Paramount) Various $6.4m $18.4m
10 (4) Hotel For Dogs (DreamWorks-Paramount) PPI $5.8m $55.2m