The origin of the increased frequency of side-effects to co-trimoxazole in HIV-positive patients is unknown. Data on plasma concentrations of the parent compounds are inconclusive. Evidence points to the hydroxylamine derivatives of sulphamethoxazole as the reactive metabolites that cause adverse reactions to co-trimoxazole. HIV-positive individuals have a systemic glutathione deficiency, and therefore a reduced capacity to scavenge such metabolites. This process would lead to an increased exposure to toxic intermediates and would explain the high frequency of adverse reactions to co-trimoxazole in these patients.