OBJECTIVE To compare the efficacy and safety of valacyclovir hydrochloride and famciclovir for the treatment of herpes zoster. METHODS A double-blind, randomized, controlled, multicenter clinical trial in which patients received 7 days of treatment and were followed up for 24 weeks. METHODS Patients reported directly to specialist centers or were referred from primary care centers. METHODS There were 597 otherwise healthy immunocompetent outpatients, aged 50 years and older, who presented within 72 hours of onset of zoster rash. METHODS Treatment with valacyclovir hydrochloride (1 g 3 times daily) or famciclovir (500 mg 3 times daily) for 7 days. METHODS Resolution of zoster-associated pain and postherpetic neuralgia, rash healing, and treatment safety. RESULTS Intent-to-treat analysis did not detect statistically significant differences for valacyclovir vs famciclovir on resolution of zoster-associated pain (hazard ratio, 1. 02; 95% confidence interval, 0.84-1.23; P =.84). Furthermore, no differences were evident between treatments on rash healing rates and on a range of analyses of postherpetic neuralgia. Safety profiles for valacyclovir and famciclovir were similar, with headache and nausea being the more common adverse events. CONCLUSIONS Valacyclovir treatment is comparable to famciclovir treatment in speeding the resolution of zoster-associated pain and postherpetic neuralgia. Current wholesale prices indicate that valacyclovir is the more cost-effective treatment for herpes zoster ($83.90 vs $140.70 per course).