BACKGROUND Approximately 45 million Americans have serologic evidence of HSV-2 infection and HSV-2 seroprevalence in the United States has increased 30% over the past two decades. Despite rapid increases in HSV-2 prevalence, the last estimate of the U.S. national direct medical cost for genital herpes (GH) was completed in 1985. The objective of this study is to assess the U.S. direct medical expenditures for GH and its complications to assist policy makers in allocating limited STD resources efficiently. METHODS We estimated the number of GH-related clinical visits and pharmacy claims from several national and state sources, estimated the average direct medical cost per visit from two administrative claims databases, and calculated the U.S. national direct medical costs for GH by applying the average direct medical cost per visit to the number of clinical visits and pharmacy claims. RESULTS The U.S. national number of GH-related clinical visits was estimated to be 499,655 and there were approximately 2,056,1180 pharmacy claims annually. Of those clinical visits, private office-based physician and public STD clinic visits alone accounted for 89%. The U.S. national direct medical costs were estimated at $166 million annually for 1992-1994, which represents $207 million in 1999 dollars. Of the total cost, medical care accounted for 36% and drug treatment for 64%. CONCLUSIONS The medical costs of pharmacy claims and office-based physician visits account for the majority of the medical expenditures for GH. Our estimates, based on the best available data on medical expenditure, indicate that GH is a major public health problem with a substantial economic burden.