We identified 36 rifampin-resistant Mycobacterium kansasii isolates, including 17 (4%) of 464 isolates recovered in Texas between 1989 and 1992. Of 29 patients infected with rifampin-resistant M. kansasii whose history of medication was known, 90% had previously received rifampin, and 58% of these patients had been treated with one or two effective drugs. Thirty-two percent of rifampin-resistant isolates recovered since 1989 were from patients who were seropositive for human immunodeficiency virus (HIV) infection. Twenty courses of therapy with a four-drug regimen determined on the basis of in vitro susceptibilities were administered to 16 patients from whom rifampin-resistant isolates were recovered; the therapy did not include surgery. Sputum cultures converted to negative as the result of 90% of treatments (time to conversion: mean, 11 weeks; range, 4-20 weeks). Bacteriologic relapses occurred in four of five patients who withdrew from therapy after being culture negative for < or = 6 months of therapy and in one of 12 patients who were culture negative for at least 12 months of therapy (mean, 16.3 months). This study suggests that the prognosis for cure of infection due to rifampin-resistant M. kansasii with chemotherapy alone is excellent, although the number of cases appears to be increasing, in part because of the HIV disease epidemic.