Recent studies have shown that ultraviolet (UV)-induced chemiexcitation of melanin fragments leads to DNA damage; and chemiexcitation of melanin fragments requires reactive oxygen species (ROS), as ROS excite an electron in the melanin fragments. In addition, ROS also cause DNA damages on their own. We hypothesized that ROS producing and metabolizing enzymes were major contributors in UV-driven melanomas. In this case-control study of 349 participants, we genotyped 23 prioritized single nucleotide polymorphisms (SNPs) in nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4 ( and , respectively), , , superoxide dismutases (, , and ) and catalase (), and analyzed their associated melanoma risk. Five SNPs, namely rs1049255 (), rs4673 (), rs10951982 (), rs8031 (), and rs2536512 (), exhibited significant genotypic frequency differences between melanoma cases and healthy controls. In simple logistic regression, rs10951982 (odds ratio (OR) 8.98, 95% confidence interval (CI): 5.08 to 16.44; < 0.001) reached universal significance ( = 0.002) and the minor alleles were associated with increased risk of melanoma. In contrast, minor alleles in rs8031 (OR 0.16, 95% CI: 0.06 to 0.39; < 0.001) and rs2536512 (OR 0.08, 95% CI: 0.01 to 0.31; = 0.001) were associated with reduced risk of melanoma. In multivariate logistic regression, rs10951982 (OR 6.15, 95% CI: 2.98 to 13.41; < 0.001) remained significantly associated with increased risk of melanoma. Our results highlighted the importance of , , and variants in the risk of melanoma.