To describe the natural history of Mycobacterium avium complex (MAC) in the respiratory or gastrointestinal tract of persons with human immunodeficiency virus (HIV) infection, 67 HIV-infected patients with CD4+ cell counts < 200/mm3 and initial negative MAC blood cultures were followed prospectively. Patients were screened every 3 months with cultures and smears of sputum, rectal swab, and blood for mycobacteria. Fourteen patients (20.9%) developed positive blood cultures for MAC (23.4%/year). Sputum cultures revealed MAC in 3 (21%) of the 14 patients at 1, 2, and 8 months before dissemination; no smears were positive. No rectal swab cultures or smears were positive before dissemination. Colonization of the respiratory and gastrointestinal tracts in persons with HIV infection and < 200/mm3 CD4+ cells is infrequently detected with currently available techniques. Screening cultures and smears of sputum and stool do not appear to be sensitive methods for detection of early MAC infection.