Study objective: To determine the pharmacokinetic parameters of acyclovirdisposition in neonates with renal dysfunction. Design: Prospective sequential open enroliment of neonates with presumed herpes group virus infections. Setting: Neonatal intensive care units in the greater Minneapolis-St. Paul metropolitanarea. Patients: Sixteen neonates with gestational ages between 27 and 40 weeks (median 38 weeks) were given acyclovir between days 1 and 56 of life to treat presumed herpes virus infections. Six infants were critically ill with multisystem disease, five infants had hepatic failure and underwent blood exchange transfusion, and five infants had renal failure. A mean of four (range 1 to 19) serum acyclovir concentrations per patient were measured by radioimmunoassay. Pharmacokinetic parameters were calculated from acyclovir concentrations in 46 samples from 16 patients. Measurements and main results: The pharmacokinetic disposition of acyclovirwas described as a two-compartment model. Although the ranges for acyclovir clearance and terminal elimination (t1/2β) were wide, a statistically, significant relationship was demonstrated between clearance and beta versus serum creatinine concentration. The average t1/2β for infants with serum creatinine level <1 mg/dl (88 μmol/L) was 5.0 hours, and 15.6 hours for those with serum creatinine level >1 mg/dl. Conclusions: Neonates with hepatic or renal dysfunction or young premature infants accumulate acyclovir when dosed without adjustment for organ dysfunction. Measurement of serum creatinine or creatinine clearance can be useful in the dosing of acyclovir in neonates.