Background: Increased oxidative stress has been linked to prostate cancer (PrCa). We investigated oxidative stress-related genetic variants in relation to advanced PrCa risk and examined potential interactions with pro- and antioxidant exposures. Methods: A case-cohort analysis was conducted in the prospective Netherlands Cohort Study, which included 58,279 men aged 55-69 years. Cohort members completed a baseline questionnaire and provided toenail clippings, which were used to isolate DNA. Advanced PrCa cases were identified during 17.3 years of follow-up. The analysis included 14 genetic variants and 11 exposures. Cox regression models were used for analysis and false discovery rate (FDR) Q-values were calculated. Results: Complete genotyping data were available for 952 cases and 1,798 subcohort members. CAT rs1001179 was associated with stage III/IV and stage IV PrCa risk, with HRs per minor allele of 1.16 (95% CI: 1.01-1.33; P=0.032) and 1.25 (95% CI: 1.07-1.46; P=0.006), respectively. We tested 151 gene-environment interactions in relation to both stage III/IV and IV PrCa risk. Seven interactions were statistically significant after adjusting for multiple testing (FDR Q-value <0.20); for stage III/IV PrCa these involved intake of beta-carotene (GPX1 rs17650792, hOGG1 rs1052133) and heme iron (GPX1 rs1800668 and rs3448), and for stage IV PrCa these involved intake of catechin (SOD2 rs4880) and heme iron (hOGG1 rs1052133, SOD1 rs10432782). Conclusion: This study of advanced PrCa risk showed a marginal association with a CAT polymorphism and seven novel gene-environment interactions in the oxidative stress pathway. Impact: Oxidative stress-related genes and exposures may have a joint effect on advanced PrCa.