Romero was scheduled to face David Branch on February 24, 2018 at UFC on Fox 28. However, on January 13, 2018, it was reported that Whittaker had pulled out of his bout against Luke Rockhold, which was scheduled to take place at UFC 221, due to an undisclosed injury. It was announced he would be replaced by Romero in what was to be a fight for the interim UFC Middleweight Championship. The winner of this bout would then face Whittaker in a unification bout. At the weigh-ins, Romero came in at 188. 3 lbs in his first attempt. He was given another two hours to make 185 lbs but failed to make weight, ending up 2. 7 pounds over the middleweight limit of 185 lbs. As a result, Romero would not have been eligible for the interim championship had he won the fight. Romero was fined 30% of his purse, which was awarded to Rockhold. If Rockhold were to win, he would still be awarded the championship. Romero won the fight via KO in the third round. Romero knocked Rockhold down with a heavy overhand followed up with a punch on the ground that rendered Rockhold unconscious.