The mechanism of action, antimicrobial spectrum, pharmacokinetic properties, drug interactions, adverse reactions and therapeutic uses of trimethoprim-sulfamethoxazole, a combination enzyme-specific inhibitor of bacterial folate synthesis, are reviewed. Trimethoprim-sulfamethoxazole currently is approved by the FDA for the therapy of established recurrent bacterial urinary tract infections, pneumocystosis, otitis media in children and shigellosis. Claimed advantages of the drug are synergistic activity, bactericidal activity and ability to decrease the rate of emergence of resistance to the individual components. Trimethoprim-sulfamethoxazole is the drug of choice for treatment of pneumocystosis and an acceptable oral therapy for recurrent urinary tract infections caused by susceptible bacteria. In children with otitis media, it is used as an alternative to ampicillin and amoxicillin and is preferred when these patients are penicillin-sensitive or when the infection is caused by beta-lactamase-producing Haemophilus influenzae. Hematologic reactions (anemia, thrombocytopenia, granulocytopenia, agranulocytosis) to trimethoprim-sulfamethoxazole occur rarely. Gastrointestinal intolerance and skin eruptions are the most prevalent adverse reactions. Most untoward reactions to trimethoprim-sulfamethoxazole develop within two weeks of onset of therapy, and their incidence compares favorably with that of standard agents administered for the same indications.