The move was a creative decision and unrelated to the sexual orientation of Smith's character, said series creator and executive producer Shonda Rhimes.
"Brooke Smith was obviously not fired for playing a lesbian. Clearly it's not an issue, as we have a lesbian character on the show -- Calliope Torres," Rhimes said in a statement Monday.
Sara Ramirez, who plays Callie, is an "incredible" actress and the goal is "to play up her magic," Rhimes said. "Unfortunately, we did not find that the magic and chemistry with Brooke's character would sustain in the long run."
The breakup's effect on Callie will be reflected in upcoming episodes, Rhimes said.
"I believe it belittles the relationship to simply replace Erica with `another lesbian,'" Rhimes said, noting that Dr. Cristina Yang (Sandra Oh) mourned the departure of Dr. Preston Burke (former cast member Isaiah Washington) for a full season.
According to a tally released in September by the Gay & Lesbian Alliance Against Defamation, ABC's fall schedule had seven characters that are either gay men or bisexual women, including the Callie and Erica characters, the most of any broadcast network.
In previous episodes, Callie has had heterosexual relationships.
Smith's departure from "Grey's Anatomy" was first reported by Entertainment Weekly.
The actress, who first appeared on the show in 2006, told the magazine she'd had high hopes for the fictional lesbian pair.
"I was very excited when they told me that Erica and Callie were going to have this relationship. And I really hoped we were going to show what happens when two women fall in love and that they were going to treat it like any heterosexual couple on TV," she said.
"And so I was surprised and disappointed when they just suddenly told me that they couldn't write for my character any more," she said.
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