The UFC announced St-Pierre (26-2) had vacated the title on Thursday. The 36-year-old is currently suffering from colitis, and said he did not wish to hold up the UFC's 185-pound division.
"My fight at UFC 217 was one of the greatest nights of my life, but I now need to take some time off to focus on my health," St-Pierre said. "Out of respect to the athletes and the sport, I don't want to hold up the division.
"I will be giving up my belt and once I'm healthy, I look forward to working with the UFC to determine what's next in my career."
As a result, interim middleweight champion Robert Whittaker has been elevated to the division's official titleholder and will face Luke Rockhold in the main event of UFC 221 on Feb. 10 in Perth, Australia.
Whittaker (19-4) won the interim championship in July by defeating Yoel Romero via unanimous decision. The 26-year-old New Zealand native aggravated a knee injury in that fight and took the rest of 2017 off.
Fighting out of Sydney, Whittaker was hopeful he'd have a chance to unify the title against St-Pierre. In a social media post last week, he told St-Pierre he was looking forward to sharing the cage with him.
Whittaker's attention will now turn to Rockhold (16-3), who is coming off a TKO win over David Branch in September.
A former UFC champion, Rockhold, 33, lost his title to Bisping at UFC 199 in June 2016. He fights out of American Kickboxing Academy and under striking coach Henri Hooft in South Florida.
The UFC 221 pay-per-view event will take place at Perth Arena.