10524 Background: The presence of functional variants of MC1R, has been shown to be associated with melanoma (MM) risk in different populations worldwide. We had previously shown in a first case - control pilot study that MC1R variants were associated the risk of melanoma (MM) in France. Methods: In order to confirm and precise these results on a larger sample, we performed a case-control study with patients from Melan-Cohort, a prospective cohort from the Paris’ region. After signature of informed consents and extraction of blood DNAs, MC1R variants were sought by automatic sequencing in 270 patients (95 familial MM, 54 multiple sporadic MM, and 121 ‘single‘ MM) and in 154 controls sex, age, and ethnic matched. Usual statistical calculations (Chi2, odd ratios, logistic regression) were carried out. Results: MC1R functional variants were present in 73% of the patients versus 43% of controls (p<0.0001). The presence of only one variant was significantly associated with melanoma risk (OR 2.9 [1.88–4.5]), and the presence of two variants doubled the risk (OR, 6.91 [3.33–14.3]). Furthermore, each of the seven variants, RHC (i.e associated with the Red Hair Phenotype; R142H, R151C, R160W, D294H) or non-RHC (V92M, V60L, R163Q) was individually associated with melanoma risk (OR ranging from 2.8 to 14). The frequency of variants was similar in each sub-group of MM examined (familial, multiple sporadic, or ‘single‘). However, RHC variants were significantly more frequent in the familial subgroup (p = 0.0045) and non RHC were significantly more frequent in the “single” MM subgroup (p = 0.0006). In addition, we confirm that the risk related to MC1R largely persisted after stratification on each clinical risk factor: hair and eyes color, skin type, and nevi count. On the other hand, there was no association between the presence of MC1R variant and the histological type of MM, the age at diagnosis, and the Breslow index. Conclusion: Our results confirm the important role of MC1R on melanoma risk in France and this independently of clinical risk factors. Surprisingly, both RHC and non-RHC variants were associated with melanoma risk, but RHC variants have possibly a higher penetrance. Finally, the presence of MC1R variants does not seem to be correlated with the speed of evolution (Breslow index) of melanoma. No significant financial relationships to disclose.