Abstract Background: In a recent study, an inverse association between diabetes and prostate-specific antigen (PSA) levels was observed, and several studies reported lower PSA levels in groups with higher body mass index. However, all of the studies were conducted in populations with intensive PSA screening and the role of diabetes severity, duration, and therapy are yet to be explored. Methods: Associations of diabetes duration and treatment, hemoglobin A1c, and BMI with PSA levels were assessed among 778 men ages 50 to 74 years, randomly chosen from the 2000 to 2002 baseline recruitment of a large population-based cohort study in Germany (prevalence of diabetes, 17%), using linear regression analyses. Results: PSA values were significantly reduced in men with insulin treatment (−39%; P = 0.006) and oral diabetic medication (−24%; P = 0.030), and in men with elevated (6.1-6.9%) and highly (≥7%) elevated hemoglobin A1c values (−15%, P = 0.004 and −29%, P = 0.003, respectively). PSA reduction was not associated with duration of diabetes. Obesity was possibly associated with a reduction of PSA levels (−14%; P = 0.096). Conclusions: Our study suggests that more severe forms of diabetes are associated with lower PSA levels and confirms the magnitude of reduction in PSA levels in diabetic men overall. The observed PSA reduction parallels reported risk reduction of prostate cancer among diabetic men. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1350–6)