Nucleobindin 2 (NUCB2) protein, a novel oncoprotein, is overexpressed in breast cancer. To date, there have been no published data regarding the role of NUCB2 protein expression in prostate cancer (PCa). Therefore, this study was performed to investigate the correlations between NUCB2 protein expression and prognosis in patients with PCa.Through immunohistochemistry, NUCB2 protein expression was evaluated in 60 benign prostatic hyperplasia (BPH) specimens and 180 PCa specimens. The correlation of NUCB2 protein expression with clinicopathological parameters was assessed using χ2 analysis. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between NUCB2 protein expression and prognosis of PCa patients.The immunohistochemistry results showed that the expression level of NUCB2 in PCa cases was significantly higher than that in BPH tissues (P < 0.001). Moreover, statistical analysis also showed that high NUCB2 protein expression was positively related to seminal vesicle invasion, lymph node metastasis, angiolymphatic invasion, higher Gleason score, biochemical recurrence (BCR), and higher preoperative prostate-specific antigen (PSA). Furthermore, it was also shown that patients with high NUCB2 protein expression had significantly poorer overall survival and BCR- free survival compared with patients with low expression of NUCB2 protein. Multivariate Cox regression analysis revealed that high NUCB2 protein expression level was an independent prognostic factor for overall survival and BCR-free survival of patients with PCa.NUCB2 protein expression showed a strong association with the potencies of BCR and progression of PCa, and that may be applied as a novel biomarker for the prediction of BCR, and helpful for improving the diagnosis, prognosis and treatment of PCa.