Famciclovir and valaciclovir were approved for use in the treatment of herpes zoster despite controversy over antiviral therapy in zoster due to high costs and uncertain benefits. To explore these issues, a Markov decision model was developed, and the incremental cost effectiveness of antiviral treatment for herpes zoster was estimated using these agents compared with no antiviral therapy. A third-party payer perspective was taken. Sensitivity analyses were performed, modeling differences in antiviral efficacy, postherpetic neuralgia (PHN) risk, and other illness parameters. Treatment of severely symptomatic acute zoster was found reasonable from a cost-effectiveness standpoint in base-case and worst-case scenarios. Treatment of mildly symptomatic acute zoster was more expensive but would likely be considered cost effective in scenarios where PHN risk was higher, PHN duration longer, or antiviral shortening of PHN greater. Further research comparing antiviral efficacy in herpes zoster is needed.