Hospitalized patients were monitored during 2,118 courses of therapy with sulfisoxazole, sulfamethoxazole, or nitrofurantoin. Overall frequency of adverse reactions severe enough to require discontinuation of the responsible drug was 3.1% for sulfisoxazole, 3.3% for sulfamethoxazole, and 9.2% for nitrofurantoin. Reaction rates were highly dependent on the duration of therapy. Toxic reactions were far more common to nitrofurantoin (5.1%) than to the sulfonamides (0.3%). They consisted mainly of gastrointestinal disturbances, were more common in women, and their frequency increased sharply with daily dose per patient weight. Sulfisoxazole was associated with allergic reactions in 2.8% of patients, sulfamethoxazole in 3.0%, and nitrofurantoin in 4.1%. Skin rashes, eosinophilia, and drug fever were the common manifestations. Serious reactions to all three drugs were rare (0.14%) and renal toxicity or immediate-type hypersensitivity reactions were not observed.