Ophidiomycosis, also known as snake fungal disease, is caused by Ophidiomyces ophidiicola and is a threat to snake conservation worldwide. Ophidiomycosis has been reported throughout much of the eastern US, and outbreaks have been associated with local population declines of already strained populations. Previous studies report significant variability in ophidiomycosis among species sampled, with higher prevalence typically observed in Nerodia spp. Although ophidiomycosis can lead to morbidity and mortality in affected individuals, little is known about disease dynamics in free-ranging populations. Herein, we examine how individual-specific factors (e.g., life stage [immature, mature], contaminant status, sex, hemograms) may be associated with ophidiomycosis status in the brown watersnake (Nerodia taxispilota). During 2018–19, we sampled 97 N. taxispilota from five locations along the Savannah River in South Carolina and Georgia, US. Ophidiomyces ophidiicola DNA was detected in 66 snakes for a prevalence of 68% (95% confidence interval, 59–77). Mature snakes had a significantly higher risk of apparent ophidiomycosis (skin lesions present and quantitative PCR [qPCR], positive) relative to immature snakes. Snakes classified as having possible (skin lesions present, but qPCR negative) or apparent ophidiomycosis exhibited a relative azurophilia and heterophilia compared with individuals classified as negative (P≤0.037). Nerodia taxispilota in this region appear to have a high prevalence of apparent ophidiomycosis (22%; 95% CI, 14–31), similar to previous reports from the southeastern US. Additional epidemiologic investigations are warranted to further elucidate other individual-specific and environmental factors that may dictate disease risk and outcomes in affected populations.