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In a controlled, prospective study, the efficacy of ritonavir 200 mg twice daily (bid) in inhibiting the decrease of amprenavir plasma concentrations caused by co-administration of lopinavir was assessed. Twelve HIV-seropositive patients were enrolled, and nine patients completed the 28-day study. At day 14, plasma concentrations of amprenavir 600 mg bid and ritonavir 200 mg bid were determined over 12 h. At day 15, lopinavir 400 mg bid was added. At day 28, plasma concentrations of amprenavir, ritonavir and lopinavir were assessed. Co-administration of lopinavir was found to decrease the amprenavir concentration, determined as the median area under the curve over 12 h (AUC12), by 25% (AUC12 24.9 microg/h/mL vs. 18.5 microg/h/mL; P<0.01), despite the presence of ritonavir 200 mg bid. Eight participants discontinued the study regimen during the first 6 weeks because of adverse gastrointestinal events. In conclusion, gastrointestinal tolerance of a regimen containing an increased dose of ritonavir 200 mg bid was low, while the regimen did not prevent a decrease of amprenavir and possibly lopinavir plasma concentrations.