Androgen deprivation therapy may increase the risk of cardiovascular disease. Limited data suggest that GnRH (gonadotropin-releasing hormone) antagonist may be associated with a lower risk of cardiovascular disease than GnRH agonist. We performed a phase II, randomized, open label study in men with prostate cancer and preexisting cardiovascular disease who were randomized to receive GnRH agonists or antagonists for 1 year. The primary outcome was endothelial function measured by the EndoPAT 2000 device (Itamar Medical, Caesarea, Israel). The predefined secondary outcome was a new cardiovascular event. Patients were followed for the development of cardiovascular disease, defined as death, myocardial infarction, a cerebrovascular event, percutaneous angioplasty with coronary stent insertion or hospitalizations due to cardiac events. A total of 80 patients were enrolled in study, including 41 and 39 who received GnRH antagonist and agonist, respectively. Patients in each arm had similar baseline characteristics. We did not detect a difference in the primary end point (endothelial function) between the groups (mean ± SD reactive hyperemia index 2.07 ± 0.15 vs 1.92 ± 0.11, p=0.42). However, during the trial period a new cardiovascular event (the secondary end point) developed in 15 patients. Of cases new major cardiovascular and cerebrovascular events developed in 9, including death in 2, myocardial infarction in 1, a cerebrovascular event in 2 and percutaneous angioplasty with coronary stent insertion in 4. Of the patients 20% randomized to GnRH agonist experienced a major cardiovascular and cerebrovascular event compared to 3% of those on GnRH antagonist (p=0.013). The absolute risk reduction in major cardiovascular and cerebrovascular events at 12 months using GnRH antagonist was 18.1% (95% CI 4.6-31.2, p=0.032). To our knowledge this is the first prospective study to test cardiovascular outcomes among patients with prostate cancer who received androgen deprivation therapy. No differences in the primary end point were noted between the study arms. However, the secondary end point revealed that patients treated with GnRH agonist experienced significantly more major cardiovascular and cerebrovascular events than those treated with GnRH antagonist. These phase II results suggest that in patients with prostate cancer who have preexisting cardiovascular disease selecting the androgen deprivation therapy modality may differentially affect cardiac outcomes.