SC-52151, an HIV-1 protease inhibitor, was developed as an ethanol-based elixir and subsequently as a self-emulsifying drug delivery system (SEDDS) to improve bioavailability. To evaluate formulation and treatment regimen effects, we conducted a four-arm, phase I/II study using the highest previously tested daily dose, 2250 mg. Forty-nine patients received the elixir or SEDDS at a dosage of 750 mg three times daily or 1125 mg twice daily for 14 days. One patient developed hypertriglyceridemia, and one had fever and dyspnea. The SEDDS formulation compared with the elixir resulted in a larger area under the concentration-time curve (AUC, p < 0.001), peak (Cmax, p = 0.041) and trough (Cmin, p = 0.025). Twice-daily administration compared with administration three times daily produced a higher cumulative AUC (p = 0.008). Both SEDDS regimens produced mean plasma concentrations above the 90% inhibitory concentration (IC90) for HIV. A mean decline of 0.03 log10 RNA copies (SEDDS) and an increase of 0.15 log10 (elixir) were observed. Although SC-52151 was well tolerated and the SEDDS formulation resulted in plasma concentrations above the IC90 for viral replication, no antiviral activity was produced.