This retrospective, unmasked chart review was undertaken to determine which HIV-infected patients receiving protease inhibitors (PIs) for the first time were most likely to experience a decrease in plasma viral load (PVL) and which factors were associated with a PVL < 500 copies/mL below the detectable limits after 6 months. A total of 308 patients aged > 15 years with a PVL > 500 copies/mL received therapy that included a PI in addition to other antiretroviral therapies (128 patients, saquinavir hard-gel capsule 600 mg TID; 107 patients, indinavir 800 mg TID; and 73 patients, ritonavir 600 mg BID). The choice of drug was at individual clinicians' discretion. Patients were followed for a median of 10 (range, 6 to 21) months. Of the 128 patients who received saquinavir, 45% were switched to another PI (33%, indinavir; 12%, ritonavir). Seventy percent of the 73 patients initially given ritonavir were switched (45%, indinavir; 25%, saquinavir), as were 23% of the 107 patients initially given indinavir (15%, saquinavir; 8%, ritonavir). A total of 34.1% (n = 105) of patients achieved a PVL < 500 copies/mL; in 51.6%, PVL decreased > 0.5 log copies/mL. In this subgroup, both treatment-naive patients and those who were receiving a new combination of antiretroviral therapy when they started PI treatment had a more pronounced decline in PVL (P < 0.001). After adjustment by logistic regression analysis for age, sex, mode of transmission, and duration of highly active antiretroviral therapy (HAART), CD4+ cell count and initial type of PI received were independently associated with PVL < 500 copies/mL. In the present study, the treatment success rate was low (34.1%) compared with rates observed in randomized, controlled trials. A higher CD4+ cell count and use of indinavir at the initiation of HAART are associated with a better viral load response.