The objective of this study is to evaluate the safety and efficacy of neoadjuvant degarelix acetate and low-dose estramustine phosphate for high-/very high-risk prostate cancer. Overall, 187 patients diagnosed with National Comprehensive Cancer Network high-/very high-risk cTanyN0M0 localized prostate cancer who consented to undergo robot-assisted radical prostatectomy after receiving neoadjuvant chemohormonal therapy for 6 months were prospectively enrolled between December 2017 and March 2023. Adverse events, perioperative and histopathological outcomes, and biochemical recurrence-free survival rates were examined. Survival analysis compared the estramustine phosphate completion and reduction groups. Thirty-six patients discontinued neoadjuvant therapy in <5 months owing to adverse events (n = 34) or other reasons (n = 2). Eleven were excluded for being in the postoperative castration range. Of the 140 patients who underwent surgery, 124 continued with two tablets of estramustine phosphate and 16 with one tablet. Overall, 82 patients were very high-risk. Histopathological outcomes were significantly worse in the very high-risk group than those in the high-risk group. Very high-risk status and estramustine phosphate reduction were significant factors in biochemical recurrence in multivariate analysis. The biochemical recurrence-free survival rate in very high-risk patients was significantly lower in the estramustine phosphate dose reduction group than in the completion group but not significant in high-risk patients. Major adverse events were anemia (n = 174), elevated transaminase levels (n = 68), and deep vein thrombosis (n = 24). Severe adverse events included acute coronary syndrome (n = 4) and pulmonary embolism (n = 3). Dose compliance with estramustine phosphate predicted biochemical recurrence in patients with very high-risk prostate cancer undergoing robot-assisted radical prostatectomy with neoadjuvant chemohormonal therapy.