The renal effects of acyclovir (100 mg/kg body weight i.p. for 7 days) were studied in rats. All animals became polyuric and presented an increase in blood urea nitrogen and fractional excretion of sodium and potassium. During hypotonic saline infusion, the acyclovir-treated rats showed higher distal fractional delivery compared to normal rats (27.8 ± 4.7 vs. 11.3 ± 0.9%, p < 0.01) and a lower ratio of free-water clearance to distal sodium delivery (33.5 ± 7.8 vs. 57.2 ± 3.9%, p < 0.02). Following hypertonic saline infusion, the ratio of osmolar to inulin clearance was higher in acyclovir rats (47.8 ± 7.4%) than in normal rats (27.0 ± 4.8%), whereas the ratio of free-water reabsorption to osmolar clearance was lower in the acyclovir rats (13.6 ± 4.6 vs. 38.2 ± 3.2%, p < 0.01). These findings suggest an effect of acyclovir on the proximal tubule, thick ascending limb and/or inner medullary collecting duct (IMCD). In vitro measurements of 3H2O permeability of perfused IMCD of normal rats showed that vasopressin (50 μU/ ml) added to the bath increased the diffusional water permeability (43.4 ± 4.8 vs. 105.6 ± 9.1×10-5 cm/s), while in acyclovir rats, the control value (58.8 ± 9.1 × 10-5 cm/s) did not increase significantly in the presence of vasopressin (71.3 ± 13.6 × 10-5 cm/s). These results suggest that high doses of acyclovir produce azotemia and an abnormal function of the proximal tubule and thick ascending limb associated with resistance to vasopres