The aim of the study was to compare the onset, incidence and frequency/intensity of hot flushes during androgen-deprivation therapy with a gonadotropin-releasing hormone antagonist (GnRH) blocker versus an agonist using data from a randomized Phase 3 clinical trial. In total, 610 prostate cancer patients received monthly degarelix (s.c., 240/80 mg, n=207, or 240/160 mg, n=202) or leuprolide (i.m., 7.5 mg, n=201) for 12 months. Data on hot flushes was collected as self-reported adverse events and in a subgroup of 254 patients with electronic diaries. The onset of hot flushes was faster on degarelix versus leuprolide, and was accompanied by higher median hot flush scores during the first 3 months. However, there were no significant differences in overall incidence rates and median hot flush scores over the entire 12 months. After the third month, incidence rates dropped below 6%, whereas prevalence rates remained constant in all the three treatment arms. In multivariate analysis, body weight and heart rate at baseline were independent predictors of hot flushes (P<0.05). Except for a more rapid onset with the GnRH antagonist, there were no major differences in the overall pattern of hot flushes between treatment options. Weight control may help to minimize the incidence of hot flushes.