To assess the efficacy of 48 weeks' treatment with saquinavir 1600 mg and ritonavir 100 mg, both given once daily (SQVOD), in drug-experienced HIV-infected patients, a SQVOD-based therapy was offered to 100 treatment-experienced patients via their own physicians. The patients starting this regimen were followed up for 48 weeks. HIV-RNA was assessed by means of NASBA (limit of quantification = 80 copies/mL). Fifteen patients received the SQVOD-based therapy. Six discontinued before week 48 because of failure, toxicity or intolerance due to the high pill burden and gastrointestinal side effects. The median baseline CD4+ cell counts and plasma HIV-RNA levels were 317 cells/microL (range 44-698) and 4.18 log copies/mL (range 2.65-6.18). At week 4, there was a mean decrease of 1.96 log copies/mL (P < 0.0001) in HIV-RNA, with 75% of the patients having fewer than 400 copies/mL; seven of the nine patients treated for 48 weeks reached fewer than 400 copies/mL. No substantial change in cholesterol or triglyceride values was observed over 48 weeks. As this SQVOD-based regimen had considerable short-term virologic activity in treatment-experienced HIV-infected patients, it may be a reasonable option when non-nucleoside reverse transcriptase inhibitors cannot be administered and once-daily dosing is preferred by the patient. However, the high pill burden and frequent gastrointestinal side effects of the soft gel capsule formulation of saquinavir may limit its long-term efficacy.