Objective:To investigate whether vitamin D receptor gene(VDR)Bsm I-rs1544410 and Fok I-rs2228570 polymorphisms,smoking duration,and body mass index(BMI)are risk factors for cutaneous melanoma,especially metastatic melanoma.Methods:We studied 120 cutaneous melanoma cases[68 stage I and II non-metastatic melanoma(NMet M)patients,plus 52Stage III and IV metastatic melanoma(Met M)patients],and 120 matching healthy controls from northeast Italy.VDR polymorphisms were measured by restriction fragment length polymorphism analysis.Absence or presence of Bsm I and Fok I restriction sites was denoted by“B”and“F”or by“b”and“f,”respectively.Results:VDR-Bsm I bb genotype was more frequent among Met M(32.7%)than among NMet M cases(13.2%),with odds ratio(OR)=3.18.Comparison of all melanoma patients vs healthy controls showed that the following biomarkers were at risk:≥20 years of smoking(OR=2.43);≥20 years of smoking combined with bb(OR=4.78),Bb+bb(OR=2.30),Ff(OR=3.04),and Ff+ff(OR=3.08);obesity(BMI>30Conclusions:Risk factors for cutaneous Met M include two VDR polymorphisms combined with smoking duration and obesity.Results suggest gene-environment implications in melanoma susceptibility and severity.Future studies in larger cohorts and in subjects with different genetic background are warranted to extend our findings. Objective: To investigate whether vitamin D receptor gene (VDR) Bsm I-rs1544410 and Fok I-rs2228570 polymorphisms, smoking duration, and body mass index (BMI) are risk factors for cutaneous melanoma, especially metastatic melanoma. Methods: We studied 120 cutaneous melanoma cases [68 stage I and II non-metastatic melanoma (NMet M) patients, plus 52 Stage III and IV metastatic melanoma (Met M) patients], and 120 matching healthy controls from northeast Italy. VDR polymorphisms were measured by restriction fragment length polymorphism analysis.Absence or presence of Bsm I and Fok I restriction sites was denoted by “B ” and “F ” or by “b ” and “f, ” respectively. Results: VDR-Bsm Ibb genotype was more frequent among Met M (32.7%) than among NMet M cases (13.2%), with odds ratio (OR) = 3.18. Comparison of all melanoma patients vs healthy controls showed that the following biomarkers were at risk: ≥20 years (OR = 2.43); Ff (OR = 3.04), and Ff + ff (OR = 3.08); ≥20 years of smoking combined with bb obesity (BMI> 30Conclusions: Risk factors for cutaneous Met M include two VDR polymorphisms combined with smoking duration and obesity. Results suggest gene-environment implications in melanoma susceptibility and severity. Future studies in larger cohorts and in subjects with different genetic background are warranted to extend our findings.