Simple SummaryMelanoma is the most severe type of skin cancer, and the risk of developing melanoma and of dying of melanoma varies between women and men. This study investigated whether widely studied genetic single nucleotide polymorphisms (SNPs) in two oncogenes known to promote cell proliferation explain these sex differences by testing such variants in a large cohort of 3663 melanoma patients. Formal analyses demonstrated that females, but not males, who carried the variantMDM4-rs4245739*C were more likely to develop a new primary melanoma, and those with the variantMDM2-rs2279744*G were less likely to succumb to the disease. We also identified a number of additional variants, often co-inherited with the tested SNPs, which modify how these and other genes work locally in the skin, as well as in distal organs where melanoma tends to spread or invade during the progression of the disease.AbstractMDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, ana priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carryingMDM4-rs4245739*C were more likely to develop multiple melanomas (ORper-allele= 1.25, 95% CI 1.03–1.51, and Ptrend= 0.03), whileMDM2-rs2279744*G was inversely associated with melanoma-death (HRper-allele= 0.63, 95% CI 0.42–0.95, and Ptrend= 0.03). We identified 16 coinherited expression quantitative loci that control the expression ofMDM2,MDM4, and other genes in the skin, brain, and lungs. Our results suggest thatMDM4/MDM2variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complexMDM2/MDM4motif, and its contribution to the tumor microenvironment and observed associations, are warranted.