Ultraviolet (UV) radiation-induced p53 activation promotes cutaneous pigmentation by increasing transcriptional activity of pro-opiomelanocortin (POMC) in the skin. Induction of POMC/alpha-melanocyte-stimulating hormone (alpha-MSH) activates the melanocortin 1 receptor (MC1R), resulting in skin pigmentation. The common p53 codon 72 polymorphism alters the protein's transcriptional activity, which may influence the UV radiation-induced tanning response.We assessed the association of the p53 codon 72 polymorphism with tanning response, and its interaction with MC1R variants on tanning response and skin cancer risk.The assessment was done in a nested case-control study within the Nurses' Health Study [219 melanoma cases, 286 squamous cell carcinoma (SCC) cases, 300 basal cell carcinoma (BCC) cases and 874 controls], and among controls from four nested case-control studies within the Nurses' Health Study.We found that the p53 Proline (Pro) allele was positively associated with childhood tanning response only among black/dark brown-haired women. Compared with the Arginine/Arginine (Arg/Arg) genotype, odds ratios (ORs) of childhood tanning tendency for Arg/Pro and Pro/Pro genotypes were 1.59 (95% CI, 0.96-2.65) and 1.56 (95% CI, 0.55-4.40), respectively. The association between MC1R variants and childhood tanning tendency was similar in both p53 Arg/Arg genotype and Pro allele carriers (Arg/Pro or Pro/Pro). The association of the p53 Pro/Pro genotype with melanoma risk was strongest among women with light pigmentation, and with MC1R variants, with the joint risk categories having the highest overall risk. We did not observe such interaction for SCC and BCC.Our study suggests the involvement of the p53 codon 72 polymorphism in the skin tanning response and potential interaction with skin pigmentation on melanoma risk. Further work is needed to evaluate the association between p53 and its associated proteins and skin cancer risk.