Hypersensitivity adverse drug reactions, characterized by fever and multi-organ involvement, are the most severe adverse reactions to sulphonamides. Although there is evidence that these reactions are initiated by metabolic events, these reactions appear to be propagated on an immune basis. We investigated the effect of a sulphonamide reactive metabolite, the hydroxylamine of sulphamethoxazole (SMX H/A), on the ability of T-lymphocytes to respond to stimulation with mitogens. Peripheral blood mononuclear cells (PBMCs) were collected and incubated with SMX H/A in increasing concentrations. PBMCs were then incubated with phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) or with PHA and ionomycin. T-lymphocyte proliferation was then determined by tritiated thymidine uptake. The hydroxylamine of sulphamethoxazole produced a concentration-dependent decrease in T-lymphocyte proliferation; this decrease was significant even at concentrations of hydroxylamine that were not associated with a decrease in cell viability. PBMCs incubated with SMX H/A that were washed and then added to fresh PBMCs failed to inhibit the proliferation of fresh PBMCs. The hydroxylamine of sulfamethoxazole produces profound suppression of T-lymphocyte proliferation. This suppression appears to be a direct event and does not involve the activation of suppressor cells. These findings may explain the infectious complications contributing to mortality associated with sulphonamide hypersensitivity reactions.