Trimethoprim-sulfamethoxazole (TMP-SMZ) has traditionally been employed as an oral formulation for infections in ambulatory pediatric patients. However, therapeutic concentrations of TMP and SMZ in serum and CSF are more consistently attained after intravenous administration. Serum half-life increases with the age of the child, and few significant toxic effects are observed with intravenous administration. Either the necessity to optimize bioavailability because of the underlying seriousness of disease or a desire to avoid other drugs that may be responsible for adverse reactions or hypersensitivity should direct the clinician to administer an intravenous preparation. Serious pediatric infections that might warrant the consideration of intravenous TMP-SMZ include shigellosis, salmonellosis, typhoid fever, nocardiosis, gram-negative bacillary septicemia or meningitis, and infections due to Pneumocystis carinii and malarial parasites. Infections due to Listeria will respond to TMP-SMZ, and infections due to Citrobacter diversus, Acinetobacter species, Pseudomonas cepacia, and Flavobacterium meningosepticum are especially susceptible to TMP-SMZ.