HIV infection results in severe immune dysfunction with ensuing sequelae that includes characteristic opportunistic infections. Pneumocystis pneumonia (PCP) is one of the most common of these infections and is routinely treated with sulphamethaxazole (SMX). Although this drug is known to cause hypersensitivity adverse drug reactions (ADRs) in 0.1% of the general population, the incidence of these ADRs increases tenfold in the HIV-positive population. The HIV-1 trans-activator of transcription (HIV-1 Tat) together with the drug metabolite sulphamethaxazole-hydroxylamine (SMX-HA) have both been reported to be factors in these hypersensitivity ADRs. In this study, we use an inducible, Tat-expressing vector system to show that the level of Tat expression contributes to the cellular sensitivity of Jurkat T cells to SMX-HA. We further demonstrated that apoptosis is the likely mechanism by which this occurs. Thus, our data provide insight into the significant increase of SMX-related ADRs during the transition between HIV-1 infection and AIDS.