The impact of highly active antiretroviral therapy (HAART) among human immunodeficiency virus (HIV)-infected patients on the incidences of mycobacterial infections has not been studied in detail. We assessed incidences of mycobacterial diseases among HIV- infected patients following the introduction of HAART, using data from the EuroSIDA study, a European, multicenter observational cohort of more than 7,000 patients. Overall incidences of Mycobacterium tuberculosis (TB) and Mycobacterium avium complex (MAC) were 0.8 and 1.4 cases/100 person-years of follow-up (PYF), decreasing from 1.8 (TB) and 3.5 cases/100 PYF (MAC) before September 1995 to 0.3 and 0.2 cases/100 PYF after March 1997. After adjustment for changes in CD4 cell count and use of antiretroviral treatment in Cox proportional hazards models, the risk of MAC decreased with increasing calendar time (hazard ratio per calendar year; HR = 0.58 [95% confidence intervals: 0.45-0.74], whereas this was not the case for TB; 0.95 [0.74-1.22]). In conclusion, we documented marked decreases in the incidence of TB and to an even larger extent of MAC among HIV-infected patients from 1994 to 1999. The decrease in TB was associated with the introduction of HAART and changes in CD4 cell count. These factors could also explain some of the decrease in MAC over time, though there remained a significantly lower risk of MAC than expected.