Trimethoprim-sulfamethoxazole (TMP-SMZ) was used for treatment of 34 patients with pulmonary or cutaneous nocardiosis. Of nine patients with primary cutaneous disease, eight had rapid resolution of their infection after short-term therapy and none have relapsed after a follow-up of more than six months. The 25 patients with pulmonary nocardiosis had a good clinical response, but three of five (60%) who completed less than three months of therapy relapsed within four weeks. Of the 10 patients who completed four to six months of therapy, only one (10%) relapsed and this relapse was due to drug resistance. By the method of serial dilution in agar, 95010 of 59 isolates of Nocardia had MICs of SMZ of <25 I-μg/ml. Fewer than 20% were susceptible to 2.5 μg of TMP/ml. Synergy between TMP and SMZ was usually present with ratios of TMP to SMZ of 1:5,1:1, or 5:1, but was less common at a ratio of 1:20. Disk susceptibility testing was easy to perform and readily separated sensitive from resistant strains. TMP-SMZ is highly effective for the treatment of nocardiosis, but the question of whether it is more effective clinically than a sulfonamide alone remains unanswered.