BACKGROUND Rofecoxib is a selective cyclooxygenase 2 (COX-2) inhibitor and is well tolerated as an alternative to nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with a previous adverse reaction to other classes of NSAIDs. Until now, there has not been information in the literature about its long-term tolerability. OBJECTIVE To provide follow-up data on patients with a history of adverse cutaneous reactions to NSAIDs who underwent and tolerated a challenge test with rofecoxib. METHODS Study patients had historically experienced cutaneous adverse reactions to aspirin and NSAIDs and had undergone single-blind challenges with rofecoxib, 25 mg. A questionnaire was distributed to all participants. In particular, they were asked to clarify any reactive symptoms they had developed after ingestion of the drug. All patients were reexamined 1 to 3 years after testing. At reexamination, they were carefully and personally interviewed using the previously distributed questionnaire. RESULTS Of the 182 patients who participated in the study, none reacted to rofecoxib during single-blind challenges. Fifty-one (28%) never received rofecoxib again, whereas 131 (72%) were exposed to rofecoxib, often on multiple occasions. Only 7 (5%) of the 131 patients reported cutaneous reactions to rofecoxib during the 3 years of follow-up. CONCLUSIONS Rofecoxib appears to be a safe alternative drug among atopic individuals, antibiotic-hypersensitive individuals, and individuals who experienced adverse cutaneous reactions to more than 1 class of NSAIDs, but it is less safe among chronic urticaria patients. Further investigations that include a larger sample are required to confirm our results especially among chronic urticaria patients.