Successful and single Beth (Kristen Bell), an art curator at the Guggenheim, is at a point in her life where love seems like a luxury she can't afford. Waiting for the "perfect" romance has embittered her. After flying to Rome to attend her younger sister Joan's (Alexis Dziena) impulsive wedding, she meets Nicholas Beamon (Josh Duhamel). He rescues her in a couple of difficult situations but they are both clumsy. Still, they hit it off.
As Beth comes to believe in love again, she sees Nick kissing another woman, who turns out to be the groom's (Luca Calvani) "crazy cousin." Slightly drunk and jealous at seeing Nick with another woman, she picks up coins (a poker chip, a rare coin, a penny, a trick quarter and a Euro) from the "fountain of love" (probably based on the Trevi Fountain). Joan tells her that legend says if you take coins from the fountain, the owner of the coin will fall in love with you.
Beth is pursued back to New York by a band of aggressive suitors whose coins she gathered, including a diminutive sausage magnate Al (Danny DeVito), lanky street illusionist Lance (Jon Heder), a doting painter Antonio (Will Arnett), and a narcissistic male model Gale (Dax Shepard). She must return the coins to the fountain to break the spell. As she falls in love with Nick, she realizes that the poker chip belongs to him and is convinced that he is under a spell, not truly in love with her.
Joan calls Beth on the day of a gala and tells her that the spell can also be broken by returning the coins to the original owner. Stacey (Kate Micucci), Beth's secretary, concerned about her, overhears the conversation and steals the coins. She believes that Beth would lead a better life with people loving her, regardless of the spell.
When Beth's suitors all show up together at her apartment, she tells them she does not love them and plans to return their coins. She also tells them of her love for Nick, but realizes that Stacey has stolen the coins. She sets off to retrieve the coins, aided by her suitors. All pile into a yellow Vespa 400 microcar (featured on the movie poster), which careens through city traffic, into a hotel and up an elevator.
Stacey returns the coins and Beth gives them back to their respective owners. Left with the poker chip, she calls Nick and thanks him for making her believe in love again. Nick makes his way to the gala to search for Beth in a sudden lightning storm that hits New York. There he happens to pick up his poker chip, dropped by Beth, and convinces her his love was true.
On Beth and Nick's wedding day in Rome, Lance tells her he had several poker chips, and Nick did not break out of the spell. While exchanging wedding vows, Beth hesitates and dashes out of the building. She revisits the fountain and wades in again.
Nick appears and joins her in the fountain. He said he had never thrown a chip in. He drops a poker chip in the water, and the priest is heard yelling, "Free of temptation!" Beth finally believes Nick and kisses him.
- Kristen Bell as Elizabeth "Beth" Martin, a successful but single curator at the Guggenheim Museum in New York City. She eventually falls in love with Nick.
- Josh Duhamel as Nick Beamon, a semi-confident and nervous man who is in love with Beth and is her primary love interest.
- Alexis Dziena as Joan, Beth's younger sister
- Peggy Lipton as Priscilla Martin, Beth and Joan's mother.
- Luca Calvani as Umberto, Joan's groom, whom she met on a business flight.
- Jon Heder as Lance, a street magician who uses his talents to try to get Beth
- Dax Shepard as Gale, a self-absorbed suitor who falls under the spell of the coins and chases Beth
- Will Arnett as Antonio, a.k.a. Anthony or Tony, a "wannabe" Italian artist who follows Beth to New York
- Anjelica Huston as Celeste, Beth's boss and director of the Guggenheim
- Kate Micucci as Stacey, Beth's co-worker and friend
- Danny DeVito as Al Russo, another one of Beth's suitors
- Don Johnson as Beth's father (uncredited)
- Bobby Moynihan as Puck
- Kristen Schaal as Alona
- Lee Pace as Brady Sacks, Beth's ex-boyfriend
- Alexa Havins as Lacey
- Efren Ramirez as Juan
Shaquille O'Neal, Lawrence Taylor and David Lee appear as themselves.
- Filming took place in Trafford, PA
- To promote the film, Don Johnson and Jon Heder co-hosted WWE's Monday Night RAW on January 18, 2010.
- The 3OH!3 music video for "Starstrukk Remix" featuring Katy Perry was set around motifs seen in and clips around When in Rome, and the song was on the film's soundtrack.
- The Friday Night Boys used clips from the movie in their music video for "Stupid Love Letter", which was featured on the movie soundtrack and in some of the previews for the movie.
The film has received negative reviews from critics. Review aggregator Rotten Tomatoes reported that 16% of critics gave the film positive reviews based on 109 reviews with an average score of 3.4/10. The consensus states that "A pair of young, attractive leads can't overcome When in Rome's reliance on unfunny gags and threadbare rom-com clichés." Review aggregator, Metacritic, which assigns a weighted average of 0–100 of the top reviews from mainstream critics, gave the film a "generally unfavorable" score of 25% from 24 reviews.
Despite negative reviews, James Berardinelli of ReelViews gave the film a fair review of 2.5/4 stars, claiming, "The saving grace of the otherwise generic product is that Bell's vivacity and Duhamel's rakish charm allow the viewer to root for them, even if sometimes that rooting goes so far as to wish the script would serve the couple better than it does."
The film was released on January 29, 2010, and opened at #3 with $12,350,041 in United States and Canada behind Avatar and Edge of Darkness. It opened in 2456 theaters, with an average of $5,029 per theater. The film grossed $32,680,633 domestically, $10,362,202 foreign and $43,042,835 worldwide.
When in Rome was released June 15, 2010, on DVD and Blu-ray Disc.