History of diabetes may be associated with decreased prostate cancer (PCa) risk. Published studies have not always accounted for time since diabetes diagnosis or confounding and effect modification by lifestyle factors. The authors investigated the relationship between diabetes and PCa risk in men in the Health Professionals Follow-Up Study from 1986 to 2004. During that time, 4,511 new PCa cases were identified. Multivariate hazard ratios (HR) were estimated using Cox regression. The HR of PCa comparing men with vs. without diabetes was 0.83 and 95% confidence interval (CI): 0.74, 0.94. PCa risk was not reduced in the first year after diabetes diagnosis (HR: 1.30, CI: 0.97, 1.72), was lower for men diagnosed for 1-6 years (HR: 0.82, CI: 0.66, 1.02), and was even lower for men who had been diagnosed for 6-15 (HR: 0.75, CI: 0.61, 0.93) or >15 years (HR: 0.78, CI: 0.63, 0.96). Reduced PCa risk was stronger in men diagnosed before 1994 (pre-PSA era) vs. after 1994. The authors also demonstrated that obese and diabetic men had a lower HR for PCa than those who were either not obese and diabetic or obese and non-diabetic. Results are consistent with the hypothesis that diabetes is associated with reduced PCa risk. Potential biological mechanisms are discussed.