Objective:To evaluate the population effectiveness of highly active antiretroviral therapy (HAART) in HIV progression and determine the heterogeneity of the effect of HAART in GEMES (Spanish multicenter study of seroconverters).Design:Multicenter cohort study.Methods:Data from 1091 persons with well-documented HIV seroconversion dates from 1980s to January 2000 were analysed. Risk of AIDS and death in subjects with same duration of HIV infection were compared in different calendar periods; before 1992, 1992–1995 (reference), 1996–1997, 1998 and 1999 with Kaplan–Meier methods and Cox proportional hazards models, allowing for late entry, fitting calendar period as time-dependent covariate and adjusting for transmission category, age and gender.Results:Statistically significant reductions in the risk of AIDS were first observed in 1998 [hazard ratio (HR), 0.59; 95% confidence interval (CI), 0.35–1.01] becoming more pronounced in 1999 (HR, 0.45; 95% CI, 0.24–0.84). Reduction in the risk of death was seen in 1997, though only reached borderline significance in 1999 (HR, 0.53; 95% CI, 0.26–1.07). Progression to AIDS and death was slower in women (HR, 0.68; 95% CI, 0.46–0.99 and HR, 0.53; 95% CI, 0.33–0.87, respectively). Compared with men who have sex with men (MSM), intravenous drug users (IDU) had lower reductions in the risk of AIDS and death.Conclusions:Reductions in incidence of AIDS and death in GEMES are seen after 1998 and 1999, respectively, compared with 1992–1995, being more pronounced in MSM compared with IDU, the commonest category in Spain.