Background: This study aims to explore the prognostic value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel therapy. Methods: We retrospectively analyzed data of 262 mCRPC patients treated with abiraterone or docetaxel as first-line therapy. NED status was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan-Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). Results: In total, NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED<10% and NED≥10%, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5-Mo vs. 10.3-Mo, P<0.001), median rPFS (mrPFS, 15.9-Mo vs. 19.5-Mo, P=0.010), and median OS (mOS, 23.2-Mo vs. 34.3-Mo, P=0.014). Likewise, for mCRPC patients receiving docetaxel-based chemotherapy, the positive detection of NED also predicted shorter mPSA-PFS (3.8-Mo vs. 5.9-Mo, P=0.052), mrPFS (8.4-Mo vs. 20.4-Mo, P=0.016) and mOS (13.6-Mo vs. 29.0-Mo, P=0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients’ survival outcomes deteriorated as the NED proportion grew in both therapies. Both abiraterone and docetaxel exerted similar and unfavorable efficacy on NED-positive mCRPC patients. Conclusions: For mCRPC patients receiving abiraterone or docetaxel treatment, NED and its proportion were critical prognostic factors. NED detection at mCRPC might aid in predicting patients’ outcomes and optimizing treatment decisions.