OBJECTIVE To investigate factors related to early virological response among a cohort of 224 patients who started a protease inhibitor (PI) for the first time. To determine which factors are associated with persistent response among patients with early response. METHODS Early complete response was defined as an undetectable plasma viral load 2 to 3 months after treatment onset (< 400 copies/ml, Quantiplex HIV 2.0 Chiron diagnostics), incomplete response as at least 1 log reduction of viral load. In patients with an undetectable plasma viral load at 2 or 3 months, we also assessed the persistence of the response on the same regimen. Virology failure was defined by two consecutive viral load levels above the detection limit. RESULTS In the total cohort, 66% of the patients had an early complete response, 11% a partial response and 23% no response. Complete virological response was significantly more frequent in naive (89%) than in pretreated (59%) patients (p < 0.001). Multivariate analysis of factors predictive of early response in pretreated patients (n = 169) showed that viral load (p = 0.001), the number of nucleoside analogs previously received (p = 0.06) and a full or partial treatment switch (p = 0.10) were associated with complete response. Analysis of later response in the 45 naive patients with prolonged follow-up showed that 22% had treatment failure after 3 to 16 months. None of the baseline variables (viral load, CD4+ cell count or nature of the PI) were associated with duration of response. The only factor associated with persistent response in pretreated patients was a low number of antiretroviral drugs previously received (log-rank test, p = 0.04). CONCLUSIONS The absence of previous antiretroviral treatment as the main factor associated with an early complete virological response. In patients pretreated with nucleoside analogs who presented early virological success, the number of drugs previously received, often associated with full or partial switch of nucleoside analog, significantly influence the persistence of response to a given triple-drug regimen.