Nimesulide is well-tolerated as an alternative to nonsteroidal antiinflammatory drugs (NSAIDs) in patients with a previous adverse reaction to other classes of NSAIDs. However, there is little information in the literature about its long-term tolerability. The study was carried out on 625 patients who had experienced adverse reactions to one or more NSAIDs. All patients received and tolerated peroral challenges with nimesulide. On the first day, patients were given an equivalent number of placebo doses to the planned number of nimesulide doses. In a successive session, the test was administered by means of increasing doses of nimesulide at 30 min intervals until the common daily therapeutic dose of 100 mg was reached (10 mg-20 mg-30 mg-40 mg). A questionnaire was distributed to all subjects. In particular, they were asked to clarify any reactive symptoms they had developed after ingestion of the drug. It was found that only 2.1% (4/192) of subjects who were given this drug experienced urticaria during treatment. We have identified three significant risk factors: a history of chronic urticaria, a history of antibiotic hypersensitivity and a history of hypersensitivity to more than one class of NSAIDs. In patients with the above risk factors, a prior tolerance test with a selective COX2 antagonist should be administered.