Sputum conversion rates in Mycobacterium avium-intracellulare (MAI) complex lung disease have ranged from only 50 to 80% despite the use of three to five antituberculosis agents. We initiated a prospective, open, noncomparative trial of initial clarithromycin monotherapy at 500 mg twice a day for 4 months in HIV-negative patients with MAI lung disease. The primary study end point was microbiologic improvement. Of 30 patients enrolled, 20 completed therapy. This latter group was predominantly male (60%), smokers (70%), older than 45 yr of age (90%), infected with Mycobacterium intracellulare (70%) and with bilateral disease (85%). Of 19 patients with pretreatment minimum inhibitory concentrations (MIC) for clarithromycin < 16 micrograms/ml, 58% became sputum-negative, and 21% showed significant reductions in sputum positivity. Heavily positive sputum cultures (> 200 colonies) were reduced from 30 to 47 samples pretherapy (64%) to three of 54 (6%) post-therapy (p < 0.0001); 18 of 19 patients (95%) showed an improvement in sputum cultures, chest radiographs, or both. Only two patients (7%) discontinued the drug because of adverse events. Only three (16%) of 19 isolates developed clarithromycin resistance (MIC > 32 micrograms/ml). Clarithromycin-susceptible and -resistant MAI isolates from the same patient had identical DNA large-restriction fragment patterns. Clarithromycin is the first single agent to be shown efficacious in the treatment of MAI lung disease.