Background Valganciclovir is the oral prodrug of ganciclovir. The pharmacokinetics of valganciclovir in patients with renal impairment is not known. Furthermore, it is not known whether there are any pharmacokinetic differences between patients who are positive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) and healthy subjects. Methods A total of 44 patients were included—18 with mild, medium, or severe renal impairment; 6 with end‐stage renal disease who were on long‐term hemodialysis;8 HIV/CMV‐positive patients with normal renal function; and 12 healthy subjects serving as controls. Valganciclovir and ganciclovir serum concentrations were measured after oral administration of 900 mg of valganciclovir. Pharmacokinetic parameters were estimated by means of noncompartmental and compartmental methods. Results After oral administration of the prodrug valganciclovir, ganciclovir bioavailability was 60% and ganciclovir concentrations were higher (maximum concentration [Cmax], 8.5 μg/mL versus 5.8 μg/mL) and appeared later (time to maximum concentration [Tmax], 4.3 versus 2.0 hours) in patients with severe renal impairment compared with healthy subjects. The elimination half‐life (t1/2)of ganciclovir was longer in patients with renal failure (t1/2 of 68.1 hours in patients with end‐stage renal disease compared with 3.5 hours in healthy subjects). Ganciclovir clearance was correlated with creatinine clearance (r = 0.975). Hemodialysis removed 50% of ganciclovir. We observed no differences in pharmacokinetics between HIV/CMV‐positive patients and healthy subjects. A 2‐compartment model with zero‐order input and first‐order elimination proved to be the most appropriate model for ganciclovir after oral administration of valganciclovir. Conclusions The dosage of valganciclovir has to be adjusted to the degree of renal impairment. Dosage adjustment is not necessary for HIV/CMV‐positive patients. Clinical Pharmacology & Therapeutics (2002) 72, 142–150; doi: 10.1067/mcp.2002.126306