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Disseminated Mycobacterium avium complex (MAC) infection is common in persons with advanced HIV infection and can be prevented by prophylactic use of rifabutin; however, routine prophylaxis is costly and incompletely effective. Chronic anemia is a common manifestation of MAC infection. We conducted a retrospective population study of the annual incidence of MAC bacteremia and blood transfusion for anemia in a regional HIV-positive population before and after the introduction of rifabutin to determine the effect of MAC prophylaxis on the incidence of transfusion-requiring anemia. The HIV-infected patient populations in 1992 and 1993 were comparable in number, severity of immunodeficiency, and zidovudine (ZDV) use. The use of rifabutin for MAC prophylaxis for those with CD4 T-lymphocyte counts < 100/microl increased from 17.2% in 1992 to 33.7% in 1993 (p < 0.001), whereas diagnostic surveillance for MAC bacteremia was stable. In 1993, there was a decrease in the number of HIV-infected persons from whom MAC was isolated (10 vs. 26, p = 0.004), and a significant decrease in the number of patients transfused for anemia (15 vs. 35, p = 0.002), number of transfusion episodes, and numbers of units transfused, associated with significant cost and resource savings. Adoption of MAC prophylaxis was followed by a significant decrease in the number of diagnosed MAC infections and in transfusion requirements in an HIV-positive population with sustained surveillance and similar levels of immunodeficiency, which may represent a health and economic benefit of effective [correction of defective] MAC prophylaxis in a population at risk.