Fans chanted "a--hole" as the man was being restrained.
The man was ejected from the theater, which seats 4,600 audience members. E! News has reached out to reps for Spears and Planet Hollywood Resort & Casino for additional comment.
Prior to the show, Spears tweeted, "Feels so good to be back in Vegas!!"
The "Make Me..." singer will return to the stage this Friday and Saturday.
Britney: Piece of Me, which debuted in December 2013, will end its four-year run on Dec. 31. "As I prepare to say goodbye to Piece of Me, I had no idea how magical this experience would be. Having my fans from around the world come see my show has been amazing," Spears told E! News in a statement four months ago. "I love Las Vegas and will miss performing this show."
Since its opening, Britney: Piece of Me has grossed over $100 million in ticket sales.