5-Chloro-2',3'-dideoxy-3'-fluorouridine (935U83) is a nucleoside analog reverse transcriptase inhibitor that has demonstrated selective anti-human immunodeficiency virus (HIV) activity in vitro and favorable safety profiles in monkeys and mice. A phase I study was conducted to evaluate the safety and pharmacokinetics of six escalating single oral doses of 935U83 in 12 HIV-infected adults. The effect of a high-fat meal on the oral bioavailability of 935U83 was also assessed. The volunteers enrolled had CD4+ cell counts ranging from < 50 to 753 cells per mm3 (median, 198). In the dose range of 100 to 1,500 mg 935U83 was well tolerated by all subjects with no drug-related adverse events reported. No significant clinical or laboratory abnormalities were observed throughout the study. 935U83 was rapidly and well absorbed following oral administration with peak plasma concentrations (Cmax) occurring at 0.8 to 1.3 h postdosing. Mean Cmax and AUC0-infinity values of 935U83 were nearly dose proportional in the 100- to 1,500-mg dose range (from 2.4 to 30 micrograms/ml and from 3.4 to 59 h.micrograms/ml, respectively). Elimination of 935U83 from the plasma was rapid, with an apparent half-life of 1.3 to 1.7 h which was independent of the dose level. Administration of 935U83 with a high-fat meal decreased the rate of 935U83 absorption (mean Cmax decreased by approximately 50% and mean time to Cmax increased by approximately 1 h) but did not affect the extent of oral bioavailability (AUC0-infinity) of 935U83. The 5'-O-glucuronide conjugate was the principal metabolite of 935U83 and was present in the plasma of all volunteers at concentrations lower than 935U83. The molar AUC0-infinity ratio (935U83 glucuronide to the parent compound) was similar across all dose levels (mean, 21 to 27%). At least 60% of the 935U83 dose was absorbed, and approximately an equal percentage of the dose (approximately 30%) was excreted as unchanged 935U83 and as 935U83 glucuronide. Systemic exposure to 935U83 at levels exceeding its average in vitro antiretroviral 50% inhibitory concentration (approximately 0.5 microgram/ml or 1.8 microM) can be achieved after a single oral dose.