Context: Once-daily HIV treatment regimens are being used in clinical practice with the objective of improving patient acceptance and adherence. Objective: To evaluate the efficacy and safety of saquinavir -soft-gelatin capsule (SGC)/ritonavir combination (1600 mg/100 mg) vs efavirenz (600 mg) both once daily and combined with 2 nucleoside analogs twice daily. Setting: Twenty-six centers in the United States, Canada, and Puerto Rico. Patients: A total of 171 antiretroviral naive HIV-infected individuals were enrolled in a 48-week, phase 3, open-label, randomized study. Main Outcome Measure: Proportion of patients with HIV-RNA levels < 50 copies/mL. The pharmacokinetic profile of saquinavir-SGC was analyzed in a subset of randomly selected patients. Results: In the primary intent-to-treat population at week 48, 51% (38/75) and 71% (55/77) of patients in the saquinavir SGC/ritonavir and efavirenz groups, respectively, achieved HIV-RNA suppression < 50 copies/ mL (P = .5392, 95% 1-confidence interval [Cl] = -33.5%). In the on-treatment (OT) population, 73% (38/52) and 93% (54/58) of patients in the saquinavir-SGC/ritonavir and efavirenz groups, respectively, had effective viral suppression < 50 copies/mL (P = .501 95% 1-sided Cl = -33.4%). Mean CD4+ cell counts increased by 239 and 204 cells/ microliters (mcL), in the saquinavir SGC/ritonavir and efavirenz groups, respectively, in the OT analysis (P = .058). Both regimens were reasonably well tolerated, although more gastrointestinal adverse events were reported with saquinavir-SGC/ritonavir. Pharmacokinet profiles in 6 patients showed an observed median Cminat 24 hours of 429 ng/ mL (range, 68-1750 ng/mL). Conclusions: Once-daily efavirenz was statistically superior to once-daily saquinavir-SGC/ritonavir. Gastrointestinal adverse effects were commonly associated with treatment failure in the saquinavir-SGC/ ritonavir arm of the study. © 2006 Medscape.