Clarithromycin 500 mg po bid or azithromycin 1200 mg po weekly is recommended as first line prophylaxis for Mycobacterium avium complex (MAC) in patients with HIV infection whose CD4 counts are <50 cells/microL. HIV-infected patients with CD4+ T-cell counts <200 cells/microL were randomized to receive either clarithromycin 500 mg po bid or azithromycin 1200 mg po weekly for 12 weeks. Nasopharyngeal swabs for Streptococcus pneumoniae and Haemophilus influenzae plus an anterior nare culture for Staphylococcus aureus were obtained at pretreatment, at 6 weeks, and at 12 weeks. A throat culture for oral flora was obtained for susceptibility testing against erythromycin. Minimum inhibitory concentrations (MICs) for clarithromycin and azithromycin were performed on all S. pneumoniae, H. influenzae, and S. aureus isolates. The study was terminated after respiratory flora, from all participants, revealed macrolide resistance. Because results of recent randomized trials indicate minimal efficacy of continuing MAC prophylaxis in patients who respond to potent combination antiretroviral therapy, the observed high incidence of macrolide-resistant bacterial colonization of the respiratory tract in this trial supports the discontinuation of macrolide prophylaxis in all AIDS patients whose CD4 counts have risen above 100 cells/microL.