Previous studies evaluated the tolerance of nimesulide and paracetamol in subjects with cutaneous, respiratory and anaphylactoid reactions induced by nonsteroidal anti-inflammatory drugs (NSAIDs). In this study we investigated tolerability and reliability of nimesulide and paracetamol in a very large number of patients with an exclusive well-documented history of NSAID-induced urticaria/angioedema. Furthermore, we evaluated whether some factors have the potential to increase the risk of reaction to paracetamol and nimesulide. A single-placebo-controlled oral challenge procedure with nimesulide or paracetamol was applied to 829 patients with a history of NSAID-induced urticaria/angioedema. A total of 75/829 (9.4%) patients experienced reactions to nimesulide or paracetamol. Of the 715 patients tested with nimesulide 62 (8.6%) showed a positive test, while of 114 subjects submitted to the challenge with paracetamol, 13 (9.6%) did not tolerate this drug. Furthermore, 18.28% of patients with a history of chronic urticaria and 11.8% of subjects with an history of NSAID-induced urticaria/angioedema or angioedema alone (with or without chronic urticaria) resulted to be intolerant to alternative drugs. Taken together, our results confirm the good tolerability of nimesulide and paracetamol in patients who experienced urticaria/angioedema caused by NSAIDs. However, the risk of reaction to these alternative study drugs is statistically increased by a history of chronic urticaria and, above all, by a history of NSAID-induced angioedema.