OBJECTIVE Fosamprenavir/ritonavir 1400 mg/100 mg once-daily regimen may have a more favourable tolerability and lipid profile than the fosamprenavir/ritonavir twice-daily regimen, while maintaining comparable antiviral efficacy. METHODS This open-label study had a group-sequential design with a stage 1 Week 24 futility analysis, with both efficacy and safety go-criteria for progression to stage 2. There were 214 antiretroviral-naive, HIV-1-infected subjects who were randomised to receive either fosamprenavir/ritonavir 1400 mg/100 mg once daily or fosamprenavir/ ritonavir 700 mg/100 mg twice daily, both with abacavir/lamivudine fixed-dose combination tablet. Primary endpoints were the proportion of subjects achieving HIV-1 RNA <400 copies/mL at Week 48 and the mean change from baseline in fasting non-HDL cholesterol. RESULTS Though stage 1 futility analysis did not meet criteria for progression to stage 2, subjects enrolled in stage 1 were followed to Week 48 per protocol. At Week 48, noninferior efficacy of once daily to twice daily (95% CI around the treatment difference, -11.4 to 9.5) was achieved, with 86/106 (81%) subjects in the once-daily and 87/106 (82%) in the twice-daily arm achieving HIV-1 RNA <400 copies/mL. Mean change from baseline at Week 48 in non-HDL cholesterol was 1.10 mmol/L and 1.26 mmol/L (p = .478) for the once-daily and twice-daily arms, respectively. CONCLUSIONS Though the study did not continue to stage 2, fosamprenavir/ritonavir once daily demonstrated noninferior antiviral efficacy to fosamprenavir/ritonavir twice daily.