Mycobacterium xenopi is infrequently recognized as a cause of pulmonary infection. We isolated this organism from 28 patients over a 3-yr period. It was nonpathogenic in 19 and pathogenic in 9. Clinical illness occurred in middle-aged men with other chronic pulmonary diseases. Therapy was associated with clinical improvement, but most isolates were resistant to first-line antituberculosis drugs. The prevalence of M. xenopi varies geographically, but in the province of Ontario, it is second to M. avium-intracellulare as the most common nontuberculous mycobacterial pathogen.