Western populations of the Italian agile frog (Rana latastei) experience widespread genetic depletion. Based on population genetic theory, molecular models of immunity and previous empirical studies, population genetic depletion predicts increased susceptibility of populations to emergent pathogens. We experimentally compared susceptibility of R. latastei populations upon exposure to an emerging strain of Ranavirus, frog virus 3 (FV3), using six populations spanning the geographical range and range of population genetic diversity found in nature. Our findings confirm this prediction, suggesting that the loss of genetic diversity accompanying range expansion and population isolation is coincident with increased mortality risk from an emergent pathogen. Loss of heterozygosity and escape from selection imposed by immunologically cross-reactive pathogens may potentially generate range-wide variation in disease resistance.