The objective of this study was to evaluate the antiretroviral efficacy and safety of ritonavir (600 mg twice a day [b.i.d.])-saquinavir (400 mg b.i.d.) compared to ritonavir (600 mg b.i.d.) in patients pretreated and receiving continued treatment with two nucleoside analogs. The study was placebo controlled, randomized, and double blind. Inclusion criteria included protease inhibitor naive status and a viral load of >10,000 copies/ml. The main end point was viral load at week 24. Forty-seven patients were included (25 given ritonavir and 22 given ritonavir-saquinavir) and monitored until week 48. At inclusion, 23% had had at least one AIDS-defining event. Previous treatment durations (mean and standard deviation) were 42 ± 25 and 37 ± 23 months, viral loads were 4.75 ± 0.62 and 4.76 ± 0.50 log₁₀ copies/ml, and CD4 cell counts were 236 ± 126 and 234 ± 125/mm³ in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, viral loads were 2.81 ± 1.48 and 2.08 ± 1.14 log₁₀ copies/ml (P = 0.04) and CD4 cell counts were 330 ± 151 and 364 ± 185/mm³ (P = 0.49) in the ritonavir and ritonavir-saquinavir groups, respectively. Similar results were observed at week 48. Moreover, at week 48, 40 and 68% (P = 0.05) and 28 and 59% (P = 0.03) of patients achieved viral suppression at below 200 and 50 copies/ml in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, six patients in the ritonavir group but only one in the ritonavir-saquinavir group had key mutations conferring resistance to protease inhibitors. Clinical and biological tolerances were similar in both groups. In nucleoside analog-pretreated patients, ritonavir-saquinavir has higher antiretroviral efficacy than and is as well tolerated as ritonavir alone.