ABSTRACT: Sea turtles are one taxon of high conservation concern that encounter many pathogens, but their disease ecology is understudied, hindering our ability to predict impacts of disease on population viability. Fibropapillomatosis (FP) is a neoplastic tumor-forming disease that has been documented in all sea turtle species, with an especially high prevalence in green turtles Chelonia mydas. Here we use Hawaiian green turtles (honu) as a study system to examine the roles of immunogenetic diversity and transcriptional modulation in sea turtle disease responses. Specifically, we quantified gene expression profiles associated with FP and characterized host diversity of major histocompatibility complex class I (MHCI) immune loci. We found 65 genes differentially expressed in blood between clinically healthy (n = 5) and FP-afflicted turtles (n = 5) with enriched biological processes of the innate immune system, aligned with expectations of reptilian immune systems and active disease resistance. Our results also suggest a role for disease tolerance in response to FP, as evidenced by enriched biological processes related to regulation of immune and metabolic homeostasis, increase in cellular detoxification, and increased tissue repair mechanisms. Honu (n = 89) had 23 unique MHCI alleles belonging to 3 distinct functional supertypes, but none were significantly associated with FP; this could be a result of intrinsic demographic properties of the population or reflect a lesser/differing role of the reptilian adaptive immune system. Our study advances the understanding of reptilian disease response and evolutionary mechanisms underlying immunogenetic diversity, both of which are important for promoting the adaptive potential of species vulnerable to extinction.