OBJECTIVE The amount of ritonavir needed to enhance saquinavir hard gel (hg) plasma concentrations is unclear. Reduced ritonavir dosing may help to reduce ritonavir-related side effects and costs. This study examined the pharmacokinetics of twice-daily saquinavir-hg (1000 mg) in the presence of ritonavir 100 mg, dosed twice-daily and once-daily on one single occasion. METHODS Eighteen HIV-infected adults taking saquinavir/ritonavir 1000/100 mg twice-daily underwent pharmacokinetic (PK) assessment of saquinavir/ritonavir on day 1 following a morning saquinavir/ritonavir dose. On day 2, PK assessment was repeated when subjects took saquinavir without ritonavir. Drug intake (with a standard meal containing 20 g of fat) was timed on days -1, 1 and 2. Geometric mean ratios (GMR) and 95% confidence intervals (CI) were calculated to assess changes in saquinavir PK parameters. RESULTS Geometric mean saquinavir AUC(0-12), C(trough), C(max) and elimination half-life on days 1 and 2 were 14 389 and 9590 ng.h/mL, 331 and 234 ng/mL, 2503 and 1893 ng/mL and 2.80 and 2.82 h, respectively. The GMR (95% CI) for these parameters were 0.67 (0.53-0.84), 0.71 (0.48-1.04), 0.76 (0.58-0.98) and 1.01 (0.86-1.18), respectively. CONCLUSIONS Withholding a ritonavir dose significantly reduces overall saquinavir exposure and C(max), but had no impact on the elimination half-life. These data establish the need to administer saquinavir and ritonavir simultaneously.