The bioavailabilities of acyclovir from capsules of valacyclovir, the L-valyl ester of acyclovir, and acyclovir were compared by measuring urinary excretion of the drug in a double blind, placebo-controlled field trial of patient-initiated treatment for recurrent genital herpes. Forty-six healthy patients with recurrent genital herpesvirus infection were randomly assigned to receive acyclovir 200 mg five times daily (n=20), valacyclovir 1000 mg twice daily (equivalent to 694 mg acyclovir twice daily) (n=18) or placebo (n=6). Thirty-three patients on the active treatments provided the required 24 h urine samples for assessment of bioavailability. The acyclovir treatment group excreted 267+/-178 mg (mean +/- SD), and the valacyclovir treatment group excreted 623+/-248 mg (mean +/- SD) acyclovir over 24 h. The mean acyclovir bioavailabilities, estimated from urinary acyclovir excretion, were 26.7+/-17.8% and 44.9+/-17.9% for acyclovir and valacyclovir, respectively (P<0.007). There was no effect of sex on acyclovir bioavailability with either drug. The relative mean bioavailability of acyclovir was 68% greater from the prodrug formulation. This field trial in patients who self-initiated treatment for recurrent genital herpes confirmed that the prodrug valacyclovir provided significantly greater acyclovir bioavailability than the parent drug, as initially shown in volunteers in clinical pharmacokinetic studies.