This was a randomized, double-blind, placebo-controlled parallel study in human immunodeficiency virus type 1 (HIV-1)-uninfected healthy subjects to investigate the pharmacokinetic interaction between indinavir (IDV) and ritonavir (RTV). Subjects were allocated to treatment groups of IDV given with RTV in the following milligram doses twice daily: 800 mg of IDV-100 mg of RTV (800-100 mg), 800-200, 800-400, and 400-400 mg, placebo of IDV with RTV doses of 100, 200, and 400 mg, and placebo of both IDV and RTV. Doses of both drugs were administered for 14 days with a low-fat meal and one dose on day 15 with a high-fat meal. Blood was obtained for drug concentration measurements on days 14 and 15. Seventy-three volunteers enrolled in the study: 29 men and 44 women. Fifty-three volunteers completed the study. When compared to standard historical data for 800 mg of IDV every 8 h (q8h), the IDV area under the concentration-time curve for 24 h (AUC(24)) of IDV-RTV regimens 400-400, 800-100, and 800-200 mg were at least 1.4, 2.3, and 3.3 times higher, respectively, regardless of meal. The concentrations at the end of the dosing interval were 10 to 25 times higher than that observed in the standard regimen of 800 mg of IDV q8h for IDV-RTV 800-100 and 800-200 mg regimens, respectively. RTV at 200 mg maximally enhanced the IDV profile. Improved tolerability was associated with IDV-RTV 800-100 mg versus IDV-RTV 800-200, 800-400, and 400-400 mg q12h. The advantages of IDV-RTV twice daily over 800 mg of IDV q8h include no food restrictions and twice-daily dosing. Also, the regimens achieve levels of IDV that may be helpful in suppressing strains of HIV-1 that have reduced susceptibility to IDV or other protease inhibitors.