Although sulfonamide therapy has reduced the case fatality rate in infection due toNocardia asteroidesfrom nearly 100% to 25% to 45% there remains a need for a still more effective chemotherapeutic regimen. We describe three cases of serious infection due toN asteroidestreated successfully with trimethoprim-sulfamethoxazole (TMP-SMX) and review an additional 15 cases from the world literature. Trimethoprim and sulfamethoxazole exhibit a synergistic interaction in vitro againstN asteroides, and the agent reaches antibacterial concentrations in blood, lung, and the central nervous system. Clinical results have been satisfactory in the limited number of patients treated to date.