Abstract Background: Thyroid hormones are hypothesized to be associated with risk of cancer because of their important role in cell differentiation, growth, and metabolism. They have also been shown to increase the proliferation of prostate cancer cells in vitro. Only one previous prospective epidemiologic study has examined circulating thyroid hormones and risk of prostate cancer, and this study provided support for the hypothesized relationship. Thus, we undertook a prospective analysis of thyroid hormones and prostate cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Methods: Within the ATBC Study, a randomized controlled trial conducted to determine the effects of α-tocopherol and α-carotene supplements on cancer incidence in male smokers, 402 prostate cancer cases were randomly sampled. Controls were matched 2:1 to cases based on age at randomization and date of blood collection. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer by quintiles of total and free thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroid-binding globulin (TBG), as well as by categories of thyroid status (i.e., hypothyroid, hyperthyroid, and euthyroid). Multivariable models were adjusted for the following factors: BMI, serum retinol, total cholesterol, α-tocopherol, and α-carotene, cigarettes per day, years smoked, family history of prostate cancer, physical activity, education, marital status, urban residence, intake of energy, dietary vitamin D, fruit, vegetables, red meat, alcohol, and supplemental calcium. Results: After multivariable adjustment, we observed that men with TSH ≤ 2.2 αIU/mL had a statistically significantly decreased risk of prostate cancer compared to men with TSH < 2.2 αIU/mL (OR=0.70, 95% CI: 0.51 - 0.97, p = 0.03). This finding was similar in relation to aggressive disease. When the T4 and TSH measurements were combined to define men as clinically or sub-clinically hypothyroid or hyperthyroid, we observed that hypothyroid men had a statistically significant lower risk of overall prostate cancer compared to men who had normal thyroid function (OR=0.48, 95% CI=0.28 - 0.81; p = 0.006). We observed no association between hyperthyroid status and risk of prostate cancer, although the number of cases in this category was small (n=9). There were too few aggressive cases who were hypothyroid or hyperthyroid to examine the association between thyroid status and disease aggressiveness. Conclusions: In this prospective study of smokers, men with elevated TSH and those classified as being in a hypothyroid state were at decreased risk of prostate cancer. Future studies should examine the association in other populations, particularly non-smokers and other racial/ethic groups, and should be large enough to evaluate the association between thyroid status and aggressive disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4472. doi:1538-7445.AM2012-4472