Background: Androgen deprivation therapy (ADT) has been associated with an increased risk of developing diabetes (DM) and cardiovascular disease (CVD), though this is controversial, particularly for CVD. We prospectively assessed the relationship between ADT and incident DM and CVD in the Prostate Cancer Outcomes Study (PCOS), a population-based cohort of prostate cancer survivors followed longitudinally for 15 years from diagnosis. Methods: We identified men in the PCOS with non-metastatic prostate cancer diagnosed from 1994 to 1995 and followed through 2009 to 2010. We used multivariable logistic regression models to compare groups receiving short-term ADT (less than 2 years), prolonged ADT (2 years or more) and no ADT to assess the relationship between ADT exposure and subsequent diagnoses of DM and CVD (determined by patient report and cause of death data). We evaluated the effects of age at diagnosis, race, stage, and comorbidity on the development of DM and CVD. Results: Among 3,526 men with comorbidity and treatment data, 2,985 men without baseline DM and 3,112 men without baseline CVD constituted the DM and CVD cohorts, respectively. Regardless of duration of ADT exposure, there was not an increased risk of DM or CVD in men younger than 70 at diagnosis. Compared to no ADT exposure, prolonged ADT was associated with an increased risk of DM and CVD that increased steadily over age 76 at diagnosis for DM (OR 2.11 at age 74, 95% CI 1.02 – 4.36; OR 2.65 at age 80, 95% CI 1.09 – 6.47) and age 74 at diagnosis for CVD (OR 1.89 at age 74, 95% CI 1.02 - 3.49; OR 3.19 at age 80, 95% 1.25 – 8.17). Increasing comorbidity burden modified risk of DM and CVD (for 3 or more comorbidities vs. no comorbidities; for DM, OR 4.25, 95% CI 2.3 - 7.9; and for CVD, OR 8.1, 95% CI 4.3 -15.5 P<0.001). Conclusions: The relationship between ADT and development of CVD and DM may be dependent upon age at diagnosis in addition to length of ADT administration, with longer ADT exposure predominantly increasing risk among older men only. Men with greater comorbid burden had increased risk of developing DM and CVD. Closer monitoring for development of DM and CVD may be most important among older men receiving prolonged ADT, especially those with other comorbidities.