AIDS Clinical Trials Group protocol 388 was designed to compare a three-drug regimen (indinavir with dual nucleosides) to a four-drug regimen (indinavir plus nelfinavir or indinavir plus efavirenz with dual nucleosides). Blood samples from patients taking indinavir and nelfinavir were collected over 8 to 12 h following a specified dose and were analyzed with high-performance liquid chromatography. Pharmacokinetic data were derived by using noncompartmental analysis. Following administration of indinavir every 8 h in the absence of nelfinavir (n = 8), the median predose indinavir concentration (C0) was 369 ng/ml (range, <10 to 949 ng/ml; one subject had a concentration of <10 ng/ml), and the concentration 8 h after administration of the study dose was 159 ng/ml (range, 85 to 506 ng/ml). In the group receiving 1,000 mg of indinavir every 12 h with nelfinavir (n = 10), the median indinavir C0 was <10 ng/ml (range, <10 to 3,740 ng/ml; six subjects had a value of <10 ng/ml), and the C12 h was 44 ng/ml (range, <10 to 4,236 ng/ml; five subjects had a value of <10 ng/ml), while the subjects who received 1,200 mg of indinavir every 12 h with nelfinavir (n = 7) had a C0 of 146 ng/ml (range, 58 to 5,215 ng/ml) and a C12 h of 95 ng/ml (range, 12 to 954 ng/ml). Indinavir clearance was significantly lower in the presence of nelfinavir (median [interquartile range], 34.1 liters/h [range, 22.6 to 45.8 liters/h] versus 47.9 liters/h [range, 42.7 to 70.3 liters/h]; P < 0.017). For subjects receiving 1,000 mg of indinavir every 12 h, the median C0 value for nelfinavir (n = 9) was 1,779 ng/ml (range, <187.5 to 4,579 ng/ml), and the C12 h was 1,554 ng/ml (range, <187.5 to 5,540 ng/ml). Due to the unacceptable number of undetectable indinavir trough concentrations, 1,200 mg of indinavir appears to be the preferred dose in a twice-daily regimen that includes nelfinavir.