Infectious diseases are causing catastrophic losses to biodiversity globally. Iridoviruses in the genus Ranavirus are among the leading causes of amphibian disease-related mortality. Polymorphisms in major histocompatibility complex (MHC) genes are significantly associated with variation in amphibian susceptibility to pathogens. MHC genes encode diverse cell-surface molecules that can recognize and bind to a wide array of pathogen peptides, and are divided into two classes. While MHC class I genes are the classic mediators of viral acquired immunity, larval amphibians do not express them. However, MHC class II gene diversity may be an important predictor of Ranavirus susceptibility in larval amphibians, the life stage most susceptible to Ranavirus. We surveyed natural populations of larval wood frogs (Lithobates sylvaticus), which are highly susceptible to Ranavirus, across 17 ponds and two years in Maryland, USA. We sequenced the peptide-binding region of an expressed MHC class IIß locus and assessed allelic and genetic diversity. We converted alleles to functional supertypes and determined if physiochemical properties of peptide-binding regions influenced host responses to Ranavirus. Among 334 sampled individuals, 26% were infected with Ranavirus, and among infected individuals the average intensity was 7.12 x 107 virus copies. We recovered 20 unique MHC class IIß alleles that fell into two deeply diverged clades and seven functional supertypes. Variation in MHC supertypes were associated with Ranavirus infection intensity, but not prevalence. MHC supertype heterozygotes and individuals with the MHC supertype genotype ST1/ST7 had significantly lower Ranavirus infection intensity compared to homozygotes and all other genotypes. We conclude that MHC class IIß functional genetic variation is an important component of Ranavirus susceptibility. Identifying immune system gene signatures linked to variation in disease susceptibility can inform mitigation strategies for combatting global amphibian declines.