One hundred twenty-three patients with nonpulmonary infections due to Mycobacterium fortuitum or Mycobacterium chelonei were treated by wound debridement and with chemotherapy on the basis of in vitro susceptibilities of the organism. Of 76 patients with infections caused by M. fortuitum, 13 required no therapy or were adequately treated with surgery alone. Patients with active localized disease received single drug therapy (usually with a sulfonamide) for a mean period of 10.6 weeks for cellulitis and seven months for osteomyelitis. Patients with extensive disease received amikacin or amikacin plus cefoxitin (mean, four weeks) followed by a sulfonamide (mean, six months). The 47 patients with infections caused by M. chelonei received no therapy or were treated with surgery alone (6); with amikacin (10), erythromycin (6), doxycycline (3), or cefoxitin (1); or with amikacin plus cefoxitin followed by cefoxitin alone for a total of 10-12 weeks (20); or other multiple-drug regimens (1). Surgery was performed on 74 (60%) patients. Schlichter tests or serum drug levels were determined for 81 (66%) patients. Response to therapy was excellent; 68 (90%) infections with M. fortuitum and 34 (72%) with M. chelonei were successfully treated. Cultures became negative within six weeks of chemotherapy, except for sternal osteomyelitis, for which cultures were not negative until up to 14 weeks. Follow-up for a mean period of 12 months following therapy was possible in 80% of cases. Relapses were rare except in patients with disseminated disease, and drug resistance developed in only one patient. These studies demonstrate the value of routine susceptibility testing of these mycobacterial species and the benefit of chemotherapy on the basis of in vitro susceptibilities.