We investigate the relation between diabetes mellitus and risk of prostate cancer among older (age 65–79 years) men in a population-based case–control study of 407 incident histologically confirmed cases registered in the South Carolina Central Cancer Registry between 1999 and 2001 (70.6% response rate); controls were 393 men identified through the Health Care Financing Administration Medicare beneficiary file for South Carolina in 1999 (63.8% response rate). After adjusting for age, race, and prostate cancer screening in the past 5 years, a history of diabetes mellitus was associated with a reduced risk of prostate cancer (adjusted odds ratio (aOR)¼0.64; 95% confidence interval (CI)¼0.45, 0.91). The protective effect was stronger for those with complications associated with diabetes (aOR¼0.61; 95% CI¼0.42, 0.90) and for African-American men (aOR¼0.36; 95% CI¼0.21, 0.62). Additional research is needed to understand the biologic mechanisms by which diabetes may influence prostate cancer risk; genetic factors may play an important role in understanding this association.