Background Globally, herpes simplex virus (HSV)-2 and-1 infections contribute to a large disease burden, but their full economic consequences remain unclear. This study aims to estimate the global economic impact of genital HSV-2 and HSV-1 infection and its consequences for people with genital ulcer disease, neonatal herpes, and human immunodeficiency virus (HIV) infection attributable to HSV-2. Methods Using a societal perspective, the economic burden was calculated at the country level and presented by World Health Organization (WHO) regions and World-Bank income levels. The disease burden was obtained from previously published global disease burden studies in 2016 and disaggregated for 194 countries. Estimates of healthcare resource utilisation were sourced from a literature review, and online interviews were conducted with 20 experts from all 6 WHO regions. Relevant costs were obtained from the literature and estimated in 2016 international dollars (I ).ResultsBothgenitalHSV-2(I 31· 2 billion) and HSV-1 (I 4·0billion)infectionsandtheirconsequenceswereestimatedtocostI 35· 3 billion globally in 2016. The major economic burden was from the Americas and Western Pacific regions combined, accounting for almost two-thirds of the global burden (I 20·8billion).High-andupper-middle-incomecountriesborealargeproportionoftheeconomicburden(76·6%orI 27· 0 billion). Costs were driven by the large number of HSV-2 recurrences; however, even assuming conservatively that people with symptomatic herpes have on average only one episode a year, global costs were estimated at I 16·5billion.ConclusionsTheglobalcostsofgenitalHSVinfectionanditsconsequencesaresubstantial.HSVpreventioninterventionshavethepotentialtoavertalargeeconomicburdeninadditiontodiseaseburden;thus,effortstoaccelerateHSVvaccinedevelopmentarecrucial.