Mycobacterium xenopi is a recognized cause of smoldering pulmonary disease in patients with chronic lung disease. This organism is frequently isolated from respiratory specimens from individuals infected with human immunodeficiency virus (HIV) and is often considered nonpathogenic. Cases of pulmonary and disseminated M. xenopi disease have been described in patients with HIV infection and other immunodeficiencies. Many physicians are unaware of the clinical significance of M. xenopi isolation. Whether this organism represents a commensal or a pathogen capable of causing considerable morbidity and mortality is not fully understood. In this study, we investigated the clinical significance of M. xenopi isolation and explored the clinical spectrum of M. xenopi disease. Clinical illness occurred both in elderly people with chronic lung disease and in young individuals with HIV infection. The repeated isolation of M. xenopi in association with pulmonary lesions suggests significant infection and mandates further workup and therapy.