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To assess the impact of highly active antiretroviral therapy (HAART) on the onset of first disseminated Mycobacterium avium complex (MAC) infection and first cytomegalovirus (CMV) disease episode in HIV-infected at-risk patients.The incidence of the two infections occurring in at-risk patients was calculated for two periods (January 1995–June 1996 and July 1996–December 1997) using the database of the HIV-infected patients followed in the Infectious Diseases Department at the Pitié-Salpêtrière Hospital in Paris. HAART was progressively introduced in late June 1996 in France.A total of 91 first disseminated MAC infections and 124 first CMV disease episodes were recorded. The incidence of first disseminated MAC infections fell from 13.4 per 100 person–years in the first 18-month period to 2.6 per 100 person–years in the second 18-month period. Similarly, the incidence of first CMV disease episodes fell from 20.9 to 3.5 per 100 person–years. Fourteen patients on HAART developed a first MAC infection, 12 (85.7%) within 2 months of starting HAART. Nineteen patients on HAART had a first CMV disease episode, 10 (52.6%) within 2 months of starting HAART.HAART led to a five-fold decrease in the incidence of first disseminated MAC infections and a six-fold decrease in first CMV disease episodes, although patients remain vulnerable to both diseases for approximately 2 months after starting HAART.