Considering the important potentiating inhibitory role of Mdm2 and of Mdm4 on cell cycle regulation and shed clarity on the inconsistent and limited body of melanoma literature, here we aimed to investigate the overall and sex-specific effect of four a priori selected candidate variants and their haplotypes, on the risk of developing subsequent primary melanomas and on disease-specific survival in a large population-based melanoma study. Here, MDM4 is linked to melanoma.