This study evaluated the risk factors for developing allergic reactions to alternative drugs such as acetaminophen and nimesulide in 367 patients intolerant of nonsteroidal anti-inflammatory drugs (NSAID) compared to 243 healthy controls. All subjects were given test doses (TD) of acetaminophen and nimesulide, and age, sex, atopy, and history of reactions also to unrelated drugs were compared in those who reacted and those who were tolerant of the challenge. TD was positive in 49 of 367 (14%) NSAID-allergic patients and in one (0.4%) of the controls (P<0.001). No difference was found in age and sex between the TD-positive and TD-negative subjects, although a significantly larger number of females were NSAID allergic (P<0.01). Of the 367 patients, 208 had a history of reactions only to NSAID, and 148 to NSAID and antimicrobial drugs (AMD). TD with acetaminophen or nimesulide was positive in 6% of patients intolerant only of NSAID and in 24% of those intolerant of both NSAID and AMD, with an odds ratio of 4.82. Atopy was more frequent among patients (36%) than controls (23%) (P=0.004), among TD-positive (51%) than TD-negative patients (33.5%) (P<0.02), and among patients intolerant of NSAID and AMD (48%) than those intolerant only of NSAID (P=0.006). The odds ratios were, respectively, 1.87, 2.57, and 3.16. This study provides evidence that atopy and history of allergic reactions to AMD increase the likelihood of intolerance of usually well-tolerated alternative drugs such as acetaminophen and nimesulide in subjects allergic to NSAID.