During 2 periods between 1997 and 1999, the Aproco-Copilote (ANRS CO 008) cohort enrolled all HIV-infected patients who began antiretroviral therapy containing a PI in 47 French centers and who volunteered to participate (1281 patients) in order to describe and analyze their long-term clinical course and the benefits of treatment. Complete adherence (more than 95% of drugs actually taken) during the first 4 months of therapy appears crucial in maintaining virological response to therapy over time. Adherence depends on how patients experience the treatment but also on external factors such as their relationship with physicians and social workers. Virological failures were classified in two groups: those sensitive to the PI prescribed and related to poor adherence (no detectable PI) or patients with resistance related to pharmacokinetic issues (detectable but insufficient PI levels). Between April 1997 and May 2004, 118 patients died, and 188 episodes of AIDS and 1178 other severe events were recorded. Follow-up at 5 years was estimated at 90% and the probability of progression towards a new episode of AIDS 16%. Risk of AIDS onset was greatest during the first year and declined thereafter. Severe morbidity unrelated to AIDS or the side effects of treatment was frequent and gradually predominated. The only patients for whom AIDS was the most frequent severe morbidity were those who started treatment with CD4 cell counts < 50/mm3. The cumulative probability of a serious antiretroviral-induced adverse event (mainly hypertransaminasemia) was 30% at 5 years; 2/3 of these events occurred during the first 6 months of follow-up. Factors associated with the 169 events attributed to the first PI prescribed included: plasma HIV RNA >100,000 copies/ml, increased transaminase levels, creatinine clearance <70 ml/min, HCV or HBV co-infection, and prescription of indinavir. Other studies are underway on the associated factors specific to each of the events to delineate the respective roles of the virus, the treatments and other factors.