Previous studies indicate that androgen deprivation therapy for prostate cancer is associated with diabetes and cardiovascular disease among older men. We evaluated the relationship between androgen deprivation therapy and incident diabetes and cardiovascular disease in men of all ages with prostate cancer. We conducted an observational study of 37,443 population-based men who were diagnosed with local or regional prostate cancer in the Veterans Healthcare Administration from January 1, 2001, through December 31, 2004, with follow-up through December 31, 2005. Cox proportional hazards models were used to assess whether androgen deprivation therapy with gonadotropin-releasing hormone (GnRH) agonists, oral antiandrogens, the combination of the two (ie, combined androgen blockade), or orchiectomy was associated with diabetes, coronary heart disease, myocardial infarction, sudden cardiac death, or stroke, after adjustment for patient and tumor characteristics. All statistical tests were two-sided. Overall, 14,597 (39%) of the 37,443 patients were treated with androgen deprivation therapy. Treatment with GnRH agonists was associated with statistically significantly increased risks of incident diabetes (for GnRH agonist therapy, 159.4 events per 1000 person-years vs 87.5 events for no androgen deprivation therapy, difference = 71.9, 95% confidence interval [CI] = 71.6 to 72.2; adjusted hazard ratio [aHR] = 1.28, 95% CI = 1.19 to 1.38), incident coronary heart disease (aHR = 1.19, 95% CI = 1.10 to 1.28), myocardial infarction (12.8 events per 1000 person-years for GnRH agonist therapy vs 7.3 for no androgen deprivation therapy, difference = 5.5, 95% CI = 5.4 to 5.6; aHR = 1.28, 95% CI = 1.08 to 1.52), sudden cardiac death (aHR = 1.35, 95% CI = 1.18 to 1.54), and stroke (aHR = 1.22, 95% CI = 1.10 to 1.36). Combined androgen blockade was statistically significantly associated with an increased risk of incident coronary heart disease (aHR = 1.27, 95% CI = 1.05 to 1.53), and orchiectomy was associated with coronary heart disease (aHR = 1.40, 95% CI = 1.04 to 1.87) and myocardial infarction (aHR = 2.11, 95% CI = 1.27 to 3.50). Oral antiandrogen monotherapy was not associated with any outcome studied. Androgen deprivation therapy with GnRH agonists was associated with an increased risk of diabetes and cardiovascular disease.