Objective To investigate the relationship between the expression level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and clinical prognosis of liver transplantation for hepatocellular carcinoma. Methods The clinical data of 94 recipients undergoing liver transplantation for hepatocellular carcinoma were retrospectively analyzed. The expression of 15-PGDH in the pathological tissues of all recipients was detected by immunohistochemical staining. The relationship between the expression level of 15-PGDH protein and clinical parameters of hepatocellular carcinoma patients was analyzed. The 5-year tumor-free survival and overall survival rates of liver transplant recipients were calculated. The possible independent risk factors of the clinical prognosis of liver transplant recipients were analyzed. Results The expression level of 15-PGDH was significantly correlated with age, Child-Pugh grade and preoperative level of alpha-fetoprotein (AFP) of the recipients (all P < 0.05). The tumor-free survival and overall survival rates of the recipients with low expression of 15-PGDH were significantly lower than those in their counterparts with high expression of 15-PGDH (both P < 0.05). The expression level of 15-PGDH, degree of tumor differentiation and American Joint Committee on Cancer (AJCC) staging were the independent risk factors of clinical prognosis of liver transplantation for hepatocellular carcinoma (all P < 0.05). Conclusions The expression level of 15-PGDH is an independent risk factor of clinical prognosis of liver transplantation for hepatocellular carcinoma.