Romero and Rockhold will compete in a five-round bout with a belt on the line as the promotion is introducing yet another interim title.
With Rockhold Vs Romero established as the new main event, UFC 221 proceeds with a card that will also feature Mark Hunt Vs Curtis Blaydes in the co-main event slot.
The man Whittaker beat to earn interim gold last summer, Yoel Romero, will take his place.
"I'm beyond disappointed that I'm unable to defend the title in my home country of Australia", Whittaker said, per Okamoto.
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With just a month to go until the event, UFC officials have moved quickly to find a replacement for Whittaker, and so Yoel Romero will now step in to fight Rockhold for the interim middleweight title in the main event instead.
The bout was going to headline UFC 221 inside Perth Arena in Perth, Western Australia.
Because of the change in main event, fans will be able to request full refunds of purchased tickets for UFC 221.
UFC Fight Night in Orlando is scheduled for February 24, with the first fights at 3:30 p.m. and the main events on the Fox network (WOFL-35 locally) beginning at 8 p.m. The victor will meet Whittaker in a title unification bout. It was the former champ's first fight since losing his middleweight belt to Bisping at UFC 199 in June of 2016. In November, former welterweight champion Georges St-Pierre returned from a four-year absence to win the title against Bisping at UFC 217.
Prior to that loss, Romero had won eight in a row, including six by knockout.