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Summary: Background: Neonatal herpes is a rare but potentially devastating condition with an estimated 60% fatality rate without treatment. Transmission usually occurs during delivery from mothers with herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) genital infection. However, the global burden has never been quantified to our knowledge. We developed a novel methodology for burden estimation and present first WHO global and regional estimates of the annual number of neonatal herpes cases during 2010–15. Methods: We applied previous estimates of HSV-1 and HSV-2 prevalence and incidence in women aged 15–49 years to 2010–15 birth rates to estimate infections during pregnancy. We then applied published risks of neonatal HSV transmission according to whether maternal infection was incident or prevalent with HSV-1 or HSV-2 to generate annual numbers of incident neonatal infections. We estimated the number of incident neonatal infections by maternal age, and we generated separate estimates for each WHO region, which were then summed to obtain global estimates of the number of neonatal herpes infections. Findings: Globally the overall rate of neonatal herpes was estimated to be about ten cases per 100 000 livebirths, equivalent to a best-estimate of 14 000 cases annually roughly (4000 for HSV-1; 10 000 for HSV-2). We estimated that the most neonatal herpes cases occurred in Africa, due to high maternal HSV-2 infection and high birth rates. HSV-1 contributed more cases than HSV-2 in the Americas, Europe, and Western Pacific. High rates of genital HSV-1 infection and moderate HSV-2 prevalence meant the Americas had the highest overall rate. However, our estimates are highly sensitive to the core assumptions, and considerable uncertainty exists for many settings given sparse underlying data. Interpretation: These neonatal herpes estimates mark the first attempt to quantify the global burden of this rare but serious condition. Better collection of primary data for neonatal herpes is crucially needed to reduce uncertainty and refine future estimates. These data are particularly important in resource-poor settings where we may have underestimated cases. Nevertheless, these first estimates suggest development of new HSV prevention measures such as vaccines could have additional benefits beyond reducing genital ulcer disease and HSV-associated HIV transmission, through prevention of neonatal herpes. Funding: World Health Organization.