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Infectious diseases are influenced by interactions between host and pathogens in variable environments and are rarely homogenous across the landscape. Areas with elevated pathogen burden and transmission may indicate a disruption to steady-state disease dynamics. However, isolating processes that result in increases in infection prevalence and intensity remains a challenge. Here we elucidate the contribution of host species, and pathogen clade in disease hotspots. We examined broad-scale patterns of infection ofO. ophidiicola, the pathogen that causes snake fungal disease, in 21 species of snakes across 10 countries in Europe. Disease hotspots were evident across several regions in Europe, and our analyses revealed significant differences in infection based on host species and pathogen clade. Over 80% of positive detections were from host species in theNatrixgenus, indicating potential higher susceptibility in this group. The presence ofO. ophidiicolagenotypes that have been associated with more severe disease in North America, also resulted in high rates of infection compared to genotypes only described from Europe. Elevated infection prevalence was best explained by an interaction between host and pathogen identity which was not uniform across all species. More broadly, these findings present important mechanisms underlying disease hotspots across a disease endemic region.