More than Jon Brion’s melancholy guitar on the spatial score, it’s The Break-Up’s Wrigley Field opening that portends a blend of laughs with realism about real-world relationships.

After a Cubs fielding mistake, Jon Favreau’s Sox fan cackles with crosstown glee at Vince Vaughn’s frustrated Cubs supporter. It’s accurate (both the blunder and the trash-talk) and funny.

Like the Cubs, Vince Vaughn is a lovable loser, and like the Cubs this season, he sure is testing his legion’s goodwill by going into an uncharacteristic funk in The Break-Up. It’s a romantic comedy smart enough to know love isn’t always funny, but might not be what people want from it.

As Vaughn’s Gary and Jennifer Aniston’s Brooke — a two-year couple that has bought a condo — call it splits and wage war over moving out, Vaughn rarely is the cuddly clown that’s made him a $12-million man. He’s still guy-humor gold, but there is a more significant abrasiveness here that could eliminate some of his female fan-base.

Plus, the Dodgeball crowd expecting non-stop zaniness is likely to loathe the film’s prolonged conclusion —eerily realistic bared-heart confessions and numbing squabbles. This Aniston-starring romantic comedy isn’t going to be as easily swallowed as Ben Stiller eating food off the street.

Perhaps meant to soften the blow, the movie is frontloaded with riotous bits where the supporting cast seems to have been intentionally directed to steal scenes. Given the unusually bland filmmaking by Peyton Reed (the bright Down With Love), that would seem to be Vaughn’s idea.

He swaps Swingers spots with Favreau, who here plays a bartending buddy with humorously bad advice. Vaughn also has parceled out his id and physical quirks to Cole Hauser and Vincent D’Onofrio, playing his brothers in a tour-bus venture. (That Vaughn never has played anyone in such a profession is either inspiration for, or self-parody of, his comic style.)

Other people with perfectly bit parts are Vaughn cronies Jason Bateman (as a diplomatic, but dubious, Realtor) and Justin Long (Brooke’s Bohemian-twit co-worker), Judy Davis as Brooke’s egomaniacal art-dealer boss and John Michael Higgins as Brooke’s brother, whose reason for waking up every morning is his a cappella group, dubbed the Tone Rangers. (Higgins even arranges a soundtrack version of “The Rainbow Connection.” Go figure.)

When they’re around, Vaughn just revs in idle and Aniston seems to be waiting around to bounce off him. By themselves, these two actors’ usual charms bubble up as they engage in petty bickering and mild games of one-upsmanship — him pulling the cord on his vocal engine, her with flustered backtalk. The back-and-forth is all along the lines of strip poker and stooge suitors, not doggie pate or attempted homicide a la War of the Roses. But this isn’t black comedy, just grayer than most.

It stumbles occasionally — with Brooke’s heavy-handed metaphor that picking art is like picking a mate and in plotting that seems predisposed to make the audience root for Gary. Brooke’s bigger person isn’t seen soon enough, and for too long, she seems like the nag Gary accuses her of being.

But their issues go beyond bowling, ballet, ballet, lemons, dishes, cleanliness, ESPN and video games, and The Break-Up is unafraid to ultimately tackle something many in the audience have lived through, but might not want to watch. With shades of Eternal Sunshine of the Spotless Mind, the conclusion has more to do with the experience of love than expectations of viewers.

In other words, people are either going to love it or hate it, despite that it’s the first mainstream romantic comedy in a long time that makes a frill-free connection with its audience. For that reason, there’s nothing wrong with something that delivers belly laughs before striking at gut level.