In the setting of human immunodeficiency virus (HIV) infection, the clinical implications of American Thoracic Society (ATS) diagnostic criteria and the significance of a single positive respiratory culture for Mycobacterium kansasii are unknown. We retrospectively studied HIV-infected patients with pulmonary M. kansasii isolated between 1989 and 2002 at one institution. Of 127 patients, 33% fulfilled ATS disease criteria. Twenty-nine percent received at least three active drugs for at least 3 months, and 53% died. In survival analysis, a lower CD4 count (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.1-2.3) and positive smear microscopy (HR, 2.8; 95% CI, 1.3-6.1) were associated with mortality, whereas antiretroviral therapy (HR, 0.3; 95% CI, 0.1-0.8) and M. kansasii treatment (HR, 0.4; 95% CI, 0.2-0.9) were associated with survival. ATS criteria did not predict mortality (HR, 0.9; 95% CI, 0.4-1.9). Fifteen patients (12%) apparently had indolent infection, not requiring immediate therapy. They had fewer positive cultures and lower rates of positive smear microscopy and ATS-defined disease. In HIV-infected patients with pulmonary M. kansasii infection, predictors of survival include higher CD4 counts, antiretroviral therapy, negative smear microscopy, and adequate treatment for M. kansasii infection, but not ATS diagnostic criteria. Withholding treatment in HIV-infected patients with respiratory M. kansasii isolates should only be considered with negative smear microscopy, few positive cultures, and mild immunosuppression.