We initiated a prospective trial of an azithromycin-containing regimen for the treatment of human immunodeficiency virus-negative patients with Mycobacterium avium complex (MAC) lung disease; the initial 4 months of therapy were with azithromycin (600 mg/d) alone. The primary study endpoint was microbiological response measured at 4 and 6 months of therapy. Of 29 patients enrolled in the study, 23 completed therapy. Fifty-two percent of these 23 patients were male, and 65% were smokers. All 23 patients were older than 45 years of age; 83% had bilateral disease, and 48% had fibrocavitary disease. Macrolide (clarithromycin)-susceptible MAC isolates were recovered from these 23 patients before treatment. Cultures of sputum from 38% of these patients became negative, and the positivity of cultures of sputum from 76% of these patients was significantly reduced. Sixty-eight percent of sputum cultures were strongly positive (> 200 colonies) before therapy, while only 27% were strongly positive after therapy. Although most patients continued to receive 600 mg of azithromycin/d, the high incidence of gastrointestinal side effects (76%) and altered hearing (41%) suggests the need for lower or less frequent dosing. Macrolide (clarithromycin) resistance did not develop in any MAC isolates during monotherapy. These results, which demonstrate that azithromycin is active against MAC pulmonary disease, provide a rationale to include this drug in the initial multidrug regimens recommended for the treatment of this disease.