The development cleared the way for Whittaker, the first Australian champion in UFC history, to make his first title defense in the headliner of the organization's first event in Perth.
After beating Romero at UFC 213, Whittaker underwent knee surgery and was unable to fight for six months.
The nature and extent of his injuries is unclear, but the show will go on.
Former middleweight champion, Luke Rockhold, will now face the #1 contender, Yoel Romero, for the UFC interim middleweight title. "I've been ruled medically unable to compete and wont be able to defend on home soil". The new main event at UFC 221 will still have championship gold resting in the balance as Rockhold vs. Romero will fight for an interim strap with the victor facing Whittaker in a unification bout later in 2018. Whittaker's interim tag was removed and he was promoted to undisputed champion in December after Georges St-Pierre vacated the middleweight title he won when he submitted Michael Bisping at UFC 217 in November.
"This card meant so much to me and I'm devastated for not being able to fight".
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.
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He ultimately dropped from being a potential top-10 to top-20 draft pick to being selected by the 49ers at No. 31. You know, when you're expecting probably to be taken much higher, that's tough on a kid.
"All I can do is focus on getting healthy to come back better than ever".
Romero had been scheduled to face David Branch on the UFC on Fox 28 card in Orlando on February 24. "All the best to Yoel and Luke for their fight and I'll be waiting..."
The 33-year-old former champion is coming off a TKO win over David Branch in September.
Losing Whittaker in this title fight is a big punch to the gut for the UFC.
The switch is yet another odd turn in the UFC's middleweight division.