Author Summary Herpes simplex encephalitis (HSE) is a rare, but severe infection of the central nervous system (CNS) caused by Herpes simplex virus type 1. We have previously characterized a model for HSE in the inbred DA rat which resembles human HSE. Interestingly the inbred PVG rat is completely resistant to the disease and displays reduced or no uptake of viral particles into the peripheral and central nerve compartments respectively. To identify the gene(s) regulating HSE pathogenesis, we crossed the susceptible DA and the resistant PVG.A rats for two generations and infected 239 rats of the F2 (DAxPVG.A) cohort with HSV-1. A genome-wide linkage scan demonstrated one strong quantitative trait locus (QTL), Hse1, on rat chromosome 4 regulating disease susceptibility. Fine mapping, haplotype mapping, sequencing and expression analysis of the genes in the Hse1 interval collectively support the underlying genetic variation to be located in, or adjacent to the calcitonin receptor gene (Calcr). Further support for a role of CalcR in regulating HSV-1 replication and propagation is provided by strain-dependent differences in the calcitonin receptor protein tissue localization and in functional studies. Using an unbiased genetic mapping approach this study identifies Calcr as a candidate for regulating susceptibility to HSE.