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Purpose: Bcl-2 family proteins are of great significance in the pathogenesis and development of tumors. In this study, the correlations between the expression of Bcl-2 family proteins and clinicopathological features and prognosis of neuroendocrine neoplasms (NENs) were further investigated. Methods: 105 Patients diagnosed with gastroenteropancreatic NENs (GEP-NENs) with the paraffin specimen of the tumor available were retrospectively included. Immunohistochemistry (IHC) was performed to detect the expression of Bcl-2 family proteins in paraffin-embedded samples. Student's t-test and Chi-square test were applied to compare the difference of quantitative and categorical variables, respectively. Survival analysis was conducted according to Kaplan–Meier method. Univariate and multivariate cox regression analysis were used to identify the independent prognostic factors. Results: The IHC score of Bcl-2 was significantly higher in neuroendocrine carcinoma (NEC) patients (65.6%), while a higher IHC score of Noxa was more common in neuroendocrine tumor (NET) patients (49.3%). Survival analysis indicated that patients with higher Bcl-2 expression and lower Noxa expression had worse 5-year survival (39.3% vs. 75.6%, p < 0.001; 40.6% vs. 84.9%, p < 0.001). Multivariate cox analysis indicated that high Bcl-2 expression was an independent factor associated with inferior DFS (hazard ratio [HR]: 2.092; 95% confidence interval [CI]: 1.106–3.955; p = 0.023) and OS (HR: 2.784; 95% CI: 1.326–5.846; p = 0.007), while higher Noxa expression was associated with superior DFS (HR:0.398; 95% CI: 0.175–0.907; p = 0.028) and OS (HR: 0.274; 95% CI: 0.110–0.686; p = 0.006). Conclusions: Higher expression of Bcl-2 and lower expression of Noxa were associated with unfavorable prognosis of GEP-NENs patients. [ABSTRACT FROM AUTHOR]