Although sulfonamide therapy has reduced the case fatality rate in infection due to Nocardia asteroides from 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 to N asteroides treated 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 against N 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.