The use of sulphonamides is complicated by a high rate of cutaneous reactions in AIDS. Metabolic risk factors have been suspected for these reactions. We conducted a prospective study to evaluate whether glutathioneS-transferase M1 null genotype, glutathione deficiency and acetylator status as risk factors. To explain the high frequency of slow acetylator phenotype in AIDS patients, we comparedN-acetyltransferase-2 phenotype and genotype in this population. AIDS patients treated with sulphonamides forPneumocystis cariniipneumonia or toxoplasmosis were followed up for cutaneous reactions. GlutathioneS-transferase genotyping, glutathione level determination,N-acetyltransferase-2 genotyping and phenotyping were performed. One hundred and thirty-six AIDS patients were studied. GlutathioneS-transferase M1 and T1 null genotypes, intracellular glutathione level, slow acetylator genotype and phenotype were not risk factors for cutaneous sulphonamides reactions. The association of glutathioneS-transferase M1 null genotype and the slow acetylator one was a risk factor [Fisher's exact test, odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.2–5.9;P= 0.02]. A discordance between acetylator genotype and phenotype was found in 35% of patients. This frequency was significantly higher than the 6–7% expected (Fisher's exact test: OR = 7.5, 95% CI = 4.2–13.4;P<0.0001). Suspected metabolic risk factors for sulphonamides cutaneous reactions were not confirmed prospectively. However, the association of glutathioneS-transferase M1 null genotype and the slow acetylator one appeared to increase the risk of reactions. We clearly showed that the acetylation phenotype measured by caffeine probe could be modified by the disease.