Genetic variation in immune-regulating components such as cytokines may lead to interindividual differences in immunosuppression response and susceptibility to melanoma. We evaluated the associations between genetic variants in five interleukins (IL) and IL receptor genes (IL-4, IL-4R, IL-6, IL-6R, and IL-10) and the risk of melanoma. Twenty-five single nucleotide polymorphisms (SNPs) were selected that are functionally relevant or tagging SNPs of each gene. We conducted a nested case-control study of 219 female patients and 219 matched controls within the Nurses' Health Study. We observed that in the IL-6R gene, four SNPs in linkage disequilibrium were associated with an increased risk of melanoma. Three are located in introns (rs6684439, rs4845618, and rs4845622), and one is a nonsynonymous SNP in exon 9 [rs8192284 (Asp358Ala)]. An elevated risk of melanoma was observed in the heterozygous groups of these SNPs with odds ratio of 1.74 [(95% confidence interval, 1.07, 2.81) for rs6684439, 1.72 (1.04, 2.84) for rs4845618, 1.69 (1.03, 2.75) for rs4845622, and 1.68 (1.04, 2.73) for rs8192284]. But these associations were not observed in the homozygous variant group with odds ratios ranging from 0.93 to 1.03. We did not find significant results for the SNPs in the other four genes. These data suggest the involvement of IL-6R in melanoma development. Further studies are needed to confirm these findings.