Background: Infection with herpes simplex virus type 2 (HSV-2) currently affects approximately 22% of adult Americans and increased markedly in prevalence between the late 1970s and early 1990s. Although some estimates of the costs of prevalent disease due to HSV-2 are available, selection of interventions to prevent HSV-2 infection, as well as evaluation of their potential cost-effectiveness, should take into account projected future costs that will result if the epidemic is left unchecked. Goal: The goal was to estimate the future health and economic consequences attributable to the HSV-2 epidemic in the absence of interventions to slow the epidemic. Study Design: A mathematical model was constructed to project future increases in HSV-2 seroprevalence in the United States. The probability of heterosexual transmission of HSV-2 was estimated from cross-sectional estimates of infection prevalence reported by the National Health and Nutrition Examination Survey (NHANES). Per-infection expected costs were calculated on the basis of data obtained from the published medical literature. Results: Without intervention, the prevalence of HSV-2 infection among individuals aged 15 to 39 years was projected to increase to 39% among men and 49% among women by 2025. Annual incidence was projected to increase steadily between 2000 and 2025, from 9 to 26 infections per 1000 men and from 12 to 32 infections per 1000 women in this age group. The cost of incident infections in the year 2000 were estimated to be $1.8 billion; the cost of incident infections was predicted to rise to $2.5 billion by 2015 and $2.7 billion by 2025. The projected cumulative cost of incident HSV-2 infections occurring over the next 25 years was estimated to be $61 billion; at a 3% discount rate, this sum has a present value of $43 billion. Conclusion: The costs of incident HSV-2 infection in the United States are substantial and can be expected to increase as both the incidence and prevalence of this disease increase in the first half of the century. The level of resource allocation for HSV-2 prevention strategies should reflect the economic benefits that would result from control of this epidemic.