The reliability and safety of the oral challenge procedure were evaluated in the diagnosis and prevention of intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs). 112 NSAID-intolerant patients were submitted to oral challenge with aspirin (acetylsalicylic acid), dipyrone, paracetamol, imidazole-hydroxybenzoate or nimesulide to confirm historic intolerance and to evaluate tolerance to other NSAIDs. A significant correlation was demonstrated between history of intolerance and the results of oral challenge in aspirin-intolerant patients (p < 0.001). Of 237 challenges with various NSAIDs and paracetamol in 101 patients, 19 challenges were positive and 2 patients developed anaphylactic shock. The ratio of positive: total challenges with alternative NSAIDs and paracetamol were as follows: 7 of 83 for paracetamol, 2 of 49 for imidazole-hydroxybenzoate and 0 of 30 for nimesulide. On the basis of these results, nimesulide was evaluated as an alternative NSAID in a second group of 284 NSAID-intolerant patients. Challenge with nimesulide elicited a positive response in 14 patients (in 6 patients the response was delayed), although adverse reactions were mild in all instances. In conclusion, a positive history of intolerance to a given NSAID is a sufficient reason to contraindicate its use even for diagnostic purposes, e.g. oral challenge. Oral challenge should therefore be restricted to the assessment of the tolerability of alternative NSAIDs. In the present study nimesulide appeared to be the safest currently available alternative in patients with NSAID intolerance.