BACKGROUND Herpes zoster (shingles) is a common disease caused by a reactivation of the latent varicella-zoster virus (chickenpox), which resides in the dorsal root ganglia. Valacyclovir HCl, the L-valyl ester of acyclovir, is an antiviral drug that is used to accelerate the resolution of the herpes zoster rash and associated pain and reduce the duration of postherpetic neuralgia. OBJECTIVE To demonstrate the safety and efficacy of oral valacyclovir 1.5 g twice daily (bid) for the treatment of uncomplicated herpes zoster in immunocompetent patients over 18 years of age. The dosing schedule of bid versus three times daily is desirable for enhancing patient compliance and to subsequently reduce the incidence of viral resistance. METHODS One treatment group of 125 patients was administered oral valacyclovir 1.5 g bid for 7 days. Administration of the first dose occurred within 72 hours after onset of rash. Patients were seen and assessed for cutaneous healing, zoster-associated pain (ZAP), and/or zoster-associated abnormal sensations (ZAAS). Patients under 50 years of age were followed for 4 weeks and patients 50 years of age and older were followed for a total of 24 weeks. Patients >or= 50 years were also asked to record a daily diary on pain and abnormal sensations throughout the 24-week study period. Responses to resource use and quality of life questions were also collected. Safety was monitored by means of routine hematologic and biochemical assessments and reporting of adverse experiences. RESULTS Data from this study were compared with historical control groups both for three times daily antiviral therapy and for placebo. The results showed that twice-daily dosing was as safe and effective as three times daily dosing for the reduction of ZAP and ZAAS. Adverse-effect profiles were similar between the two different regimens, and both treatment groups showed better outcomes than the historical placebo group. Because it is standard of care to administer antivirals for the treatment of acute herpes zoster, a placebo-controlled trial is not possible, necessitating the use of historical controls. CONCLUSIONS Oral valacyclovir 1.5 g bid is safe and effective for the treatment of uncomplicated herpes zoster in immunocompetent patients over 18 years of age. Twice-daily dosing may help increase patient compliance and therefore increase the effectiveness of treatment of the acute herpes zoster rash and the prevention of ZAP.