Abstract Background: Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental, and host characteristics and their interactions contributing to risk. Recently, gene-specific promoter methylation in blood has been associated with the risk of several cancers including breast, lung and pancreatic. We thus examined whether gene-specific promoter methylation was associated with risk of CMM in individuals from melanoma-prone families. Methods: We measured the promoter methylation status of 15 genes (CDH1, COL1A2, DAPK, DDIT4L, HSPB6, LOX, MT1G, NPM2, p14, p16, PTEN, RASSF1, MAGEA3, TNFRSF10C and TNFRSF10D) previously shown to be aberrantly methylated in melanoma tumors using bisulfite pyrosequencing at 65 CpGs in peripheral blood mononuclear cells (PBMCs) from 236 individuals (114 melanoma cases and 122 unaffected individuals) in 64 melanoma-prone families. For functional validation we obtained gene expression data for 14 out of the 15 genes through independent expression profiling analysis. We also compared the values from each methylated promoter to mRNA expression. We used logistic regression to evaluate the association between CMM status and average promoter methylation controlling for age, sex and adjusting variance for familial correlation. Results: In unaffected individuals, overall promoter methylation levels were low for most of these genes in blood. Only TNFRSF10C (P=0.009) and TNFRSF10D (P=0.010) showed the expected negative correlation between promoter methylation and gene expression. Therefore, we focused on these two genes in subsequent analyses. Compared to controls, CMM cases had significantly lower promoter methylation at TNFRSF10C (P= 0.002) and TNFRSF10D (P=0.045). This difference remained significant after further adjusting for CDKN2A, dysplastic nevi and pigmentation characteristics. Significance: TNFRSF10C and TNFRSF10D encode separate decoy death receptors, whose overexpression in both normal and malignant cells can inhibit apoptosis. Our findings support a potential association between reduced promoter methylation of TNFRSF10C and TNFRSF10D in blood and risk of CMM in our melanoma-prone families. Citation Format: Paula L. Hyland, Laura S. Burke, Ruth M. Pfeiffer, Margaret A. Tucker, Alisa M. Goldstein, Xiaohong R. Yang. Promoter methylation of death receptor decoy genes in blood and risk of melanoma in melanoma-prone families . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 688. doi:10.1158/1538-7445.AM2013-688