OBJECTIVES: Previous analyses have shown that antiviral therapy for herpes zoster is economically reasonable, however much of the effect comes from moderation of postherpetic neuralgia (PHN), particularly in the elderly. Effective medications to ameliorate PHN are now available, but their impact on antiviral cost-effectiveness is unclear. METHODS: We modified our previous zoster/PHN model to consider PHN therapy in 70 year-olds. We used this model to estimate the cost-effectiveness of antiviral therapy in the presence of effective PHN therapy. A societal perspective was taken, using reference case recommendations of the Panel on Cost-Effectiveness in Health and Medicine. We assumed that antivirals lessened acute zoster symptoms and decreased PHN duration, but not its likelihood or severity. PHN therapy side effects were not considered, biasing the analysis against antivirals. Mild and severe acute zoster scenarios were considered, with utilities of 0.9 and 0.7 respectively on a 0=death and 1=perfect health scale. RESULTS: If effective PHN therapy is not available, antiviral therapy costs $47,300 per quality-adjusted life year (QALY) gained for mild acute zoster and $18,800/QALY for severe acute zoster. When gabapentin is the PHN therapy considered (34.5% pain relief, average wholesale price $197/mo.), antiviral therapy of mild zoster costs $40,600/QALY and severe acute zoster treatment cost $11,300/QALY. For mild zoster, antivirals plus PHN therapy cost more per QALY than antivirals alone when PHN therapy pain relief is >60%, costing $64,700 with 100% relief. For severe zoster, antivirals plus PHN therapy cost less than antivirals alone even when PHN relief is 100% (costing $14,700/QALY). Other PHN therapies show similar effects. CONCLUSIONS: PHN therapy has little impact (except for mild improvement) on the cost-effectiveness of antiviral therapy for herpes zoster, due to relatively low reported levels of pain relief (<40%) as well as longer PHN duration and loss of acute zoster relief when antivirals are not used.