Few studies have considered etiological differences across molecular subtypes of prostate cancer, despite potential to improve opportunities for precision prevention of a disease for which modifiable risk factors have remained elusive. Factors that lead to DNA double-strand breaks, such as oxidative stress, may promote the formation of the TMPRSS2:ERG gene fusion in prostate cancer. We tested the hypothesis that increasing levels of pre-diagnostic circulating antioxidants, which may reduce oxidative stress, are associated with lower risk of developing TMPRSS2:ERG positive prostate cancer.We conducted a nested case-control study, including 370 cases and 2,470 controls, to evaluate associations between pre-diagnostic α- and β-carotene, α- and γ-tocopherol, β-cryptoxanthin, lutein, lycopene, retinol, and selenium with the risk of prostate cancer by ERG protein expression status (a marker of TMPRSS2:ERG). Multivariable unconditional polytomous logistic regression was used to calculate odds ratios and 95% confidence intervals.We did not find any of the antioxidants to be significantly associated with the risk of prostate cancer according to ERG status.The results do not support the hypothesis that circulating pre-diagnostic antioxidant levels protect against developing TMPRSS2:ERG positive prostate cancer. Additional studies are needed to explore mechanisms for the development of TMPRSS2:ERG positive disease. Prostate 77: 647-653, 2017. © 2017 Wiley Periodicals, Inc.