Sex differences in melanoma are prominent, with female having a significant survival advantage. However, it is unclear why we see this survival advantage. Here, we investigate the relationship between sex, clinicopathologic variables, and melanoma specific survival in 1753 single primary melanomas from patients in the GEM (Genes, Environment, and Melanoma) study. Using Cox proportional hazard models and formal mediation analysis, the effect of sex on survival is explained largely by differences in the clinicopathologic features of tumors at diagnosis. Specifically, we find evidence that 86.5% of the effect of sex on melanoma survival is mediated by differences in age at diagnosis, Breslow thickness, ulceration, mitoses, and site (hazard ratio [HR] = 1.85, P <
.001). This analysis indicates that the female survival advantage in melanoma is not primarily due to a direct effect of sex (HR = 1.19, P = .42) but is largely a result of an indirect effect of sex mediated by clinicopathologic features.