Concentration-targeted (C) strategies may reduce pharmacologic variability, which has been suggested as one factor in the heterogeneity in antiretroviral response. Methods: Antiretroviral-naive persons are randomized to standard dose therapy (S) with ZDV, 3TC, and IDV, or a C regimen. Targets are: ZDV, Css≥0.19 mg/L; 3TC, Css≥0.44 mg/L; and IDV, C8h≥0.15 mg/L. Serial concentrations are measured after 2 wks and parameters determined with Bayesian-estimation; dose adjustments are performed in C recipients to achieve desired targets. Single timed concentrations are measured every 4 weeks and compared with predicted allowing for possible analytical and dose-sample timing errors. Results: Data are available for 24 patients, 13 S and 11 C. Oral clearance of ZDV, 3TC, and IDV at wk 2 was not different between S vs C; overall mean values (L/h/kg) were: ZDV, 2.15±1.1; 3TC, 0.36±0.09; IDV, 0.74±0.29. After dose adjustments, average values (mg/L) achieved with C were: ZDV, Css=0.21; 3TC, Css=0.46; and IDV, C8h=0.17. C therapy reduced variability in ZDV Css by 54%, and 3TC by 24%; IDV C8h were higher in C vs S (0.17 vs 0.06 mg/L, p=0.01). In 10 patients with 6 mo of C therapy, the median % of samples ≥ target was: ZDV, 100%; 3TC, 100%; IDV, 83%. Conclusions: C therapy with ZDV, 3TC, and IDV is feasible and reduces inter-patient variability in systemic exposure.