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This study assessed the efficacy of short-course induction treatment with saquinavir/ritonavir as boosted protease inhibitor monotherapy in antiretroviral-naive patients, before switching to conventional highly active antiretroviral therapy. Twenty-eight patients were enrolled, with baseline CD4 cell counts of 26 cells/μl and HIV RNA 5.5 log10 copies/ml. There was a median 2.5 log10 reduction in HIV RNA and 115 cell increase in CD4 cell counts after 4–8 weeks of saquinavir/ritonavir monotherapy. This treatment strategy should be evaluated further.