A comprehensive review is presented of the world literature on adverse reactions to trimethoprim- sulfamethoxazole (TMP-SMZ) since its first use in 1968, when concern was expressed about possible hematologic toxicity. Serious toxicity is a rare event, but when it occurs severe skin lesions and thombocytopenia/leukopenia are the most likely complications. Like other antibacterial agents, TMP-SMZ is associated with gastrointestinal upset, but adverse reactions affecting the kidney, liver, and fetus are rare. If the use of TMP-SMZ in pregnant women and in those known to be sensitive to the drug is avoided and if there is an awareness of possible drug interactions, therapy with the combination in the usual clinical setting is not associated with serious toxicity.