BACKGROUND Patients with aspirin-sensitive respiratory disease experience cross-reactions to all nonsteroidal anti-inflammatory drugs, which inhibit cyclooxygenase enzymes. With the introduction of antiarthritis drugs, which selectively inhibit cyclooxygenase-2, questions are raised as to whether cross-reactivity occurs between aspirin and these new cyclooxygenase-2 inhibitors. OBJECTIVE The goal of this study was to determine whether rofecoxib cross-reacts in aspirin-sensitive patients with asthma. METHODS Sixty patients with asthma underwent doubleblinded, placebo-controlled oral challenges with rofecoxib (12.5 mg, 25 mg, and 2 placebos) over 48 hours in our General Clinical Research Center. The next day, aspirin sensitivity was proven in each of the 60 patients through use of single-blinded oral aspirin challenges. RESULTS None of the 60 patients experienced any symptoms, changes in nasal examination findings, or declines in FEV(1) values during their challenges with rofecoxib. All 60 patients experienced typical naso-ocular and asthmatic reactions to aspirin with a mean provoking dose of 61 mg. The exact 1-sided CI for the probability of rofecoxib inducing crossreactions in aspirin-sensitive patients with asthma is calculated to be between 0% and 0.05%. CONCLUSIONS Given that none of the 60 patients reacted to rofecoxib and given the statistical power of this large sample size, we conclude that cross-reactivity between aspirin and rofecoxib does not occur in patients with aspirin-sensitive respiratory disease. This does not exclude rofecoxib from participating in other types of reactions, including immune recognition after prior treatment with the drug. From the standpoint of the mechanisms involved in aspirin-induced respiratory reactions, this study strongly supports inhibition of cyclooxygenase-1 as the essential initiator of these types of reactions.