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Purpose: The aim of this study was to elucidate the prognostic value of proenkephalin (PENK) in gastrointestinal stromal tumors (GISTs). Patients and methods: We collected data on 268 eligible postoperative patients diagnosed with GIST between January 1, 2002, and December 31, 2011. PENK expression was detected in GIST tissues classified using the United States National Institutes of Health (NIH) risk classification system. The associations between high PENK expression and the clinicopathological characteristics were assessed. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan–Meier analysis, and the log-rank test was used to compare the differences between groups. Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of PENK in GIST patients. Results: High PENK expression was more common in the low- and intermediate-risk GIST groups compared with the high-risk group (P<0.05). Additionally, PENK expression was associated with tumor size, mitosis count per 50 high-power fields, and tumor rupture (P<0.05). Kaplan–Meier analysis revealed that high PENK expression was associated with superior OS and RFS, while low PENK expression was associated with worse OS and RFS. Furthermore, PENK was shown to be an independent predictor of OS and RFS in the overall population (for OS, hazard ratio [HR], 1.596, 95% confidence interval [CI], 1.006–2.914, P<0.001; for RFS, HR, 1.910, 95% CI, 0.977–3.089, P<0.001). Conclusion: PENK expression in GIST is closely associated with NIH risk grade and prognosis, indicating that PENK may act as a tumor suppressor and may serve as a new biomarker for predicting prognosis in postoperative GIST patients. [ABSTRACT FROM AUTHOR]