Sequential use of antiretroviral therapy with protease inhibitors (PI) is frequently prescribed owing to failure or intolerance of the first selected agent. Controversial data exist about the virological and immunological outcome of patients in whom a change to a second PI regimen is needed. A prospective study of 113 HIV-positive patients (male, 84%; mean age 36 years; previous AIDS-defining event, 35%; previous antiretroviral therapy with nucleoside analogues, 94%) who started a saquinavir-containing regimen between March 1996 and March 1997 and had to change to indinavir (n = 79) owing to intolerance, failure or medical criteria was performed. At the time of the switch, median CD4 cell count was 221 cells/mm3 and the HIV RNA level was 3.98 log10 copies/ml. The rate of viral suppression (HIV RNA levels below 200 copies/ml) was 40% at 3 months and 28% at month 6 after indinavir was instituted. In a logistic regression analysis, only the baseline viral load [relative risk (RR), 2.85; 95% confidence interval (CI), 1.31-6.05; P = 0.007] was statistically associated with the lack of viral suppression on indinavir. Although there are not sufficient data about the best therapeutic option if a change in PI-containing regimens therapy is considered, this study supports the recommendation of an early change of the PI-containing regimens, before the HIV-1 viral load reaches high levels.