Objectives: To examine survival and progression to AIDS among HIV-infected patients after starting highly active antiretroviral therapy (HAART). Methods: The study population consisted of 3724 patients from the ATHENA observational cohort who initiated HAART. We considered progression to either an AIDS-defining disease or death, distinguishing HIV-related and non-related (including therapy-related) deaths. A time-dependent multivariate hazards model was fitted to the patient data and 5-year survival probabilities under various therapy scenarios estimated. Results: A total of 459 patients developed AIDS and 346 died during 12 503 person-years of follow-up. HIV-related mortality decreased from 3.8 to 0.7 per 100 person-years between 1996 and 2000 whereas non-HIV-related mortality did not change (0.4 and 0.9, respectively, P = 0.25). For asymptomatic and symptomatic therapy naive patients younger than 50 years with CD4 counts above 10 × 106 and 150 × 106 cells/l, respectively, predicted 5-year survival probabilities were above 90% when HAART was used continuously. This limit was 450 × 106 cells/l when HAART was used during 20 weeks in each 24 week-period of follow-up, and 110 × 106 cells/l when patients delayed initiation of HAART for 1 year after becoming eligible for treatment. Conclusions: Survival probabilities were high among HIV-infected patients initiating HAART at an early stage of infection. The best therapy strategy is therefore to start HAART at this stage of infection. However, deferring HAART in patients with high CD4 cell counts may be clinically more appropriate given toxicity and adherence problems. The lack of any change in non-HIV-related mortality suggests that toxicity has not yet become a major risk factor for death.