As a tumor suppressor candidate gene, NPRL2 has anticancer effects against several cancers, but its potential role in prostate cancer (PCa) has not been reported. The present study aimed to explore the expression of NPRL2 in PCa and its potential clinical significance. Our results showed that expression of NPRL2 in PCa tissues was significantly higher than that in non-PCa tissues (P < .001). High NPRL2 expression in PCa tissue was significantly correlated with a high Gleason grade group (P < .001), high pT stage (P < .001), and lymph node metastasis (P = .003). The overall survival of PCa patients with negative to weak NPRL2 expression was significantly higher than that of patients with moderate to strong positive NPRL2 expression. Furthermore, in vitro, we found that the up-regulated NPRL2 level in LNCaP and PC3 cells, and forced reexpression of NPRL2 significant promoted the growth of those cells and vice versa. Contrary to existing reports, our results interestingly showed, for the first time, that the expression level of NPRL2 was significantly up-regulated in PCa and its high expression was correlated with poor prognosis, suggesting its pivotal role in the progression of PCa. NPRL2 may serve as a potential prognostic biomarker for PCa patients.