Cyclooxygenase-2 (COX-2) influences carcinogenesis through regulation of angiogenesis, apoptosis, cytokine expression, and immune response suppression. It has been well established that COX-2 is overexpressed in a variety of human cancers, such as hepatocellular carcinoma (HCC). In this study, we aimed to evaluate the association between COX-2 polymorphisms and prognosis of HCC. We genotyped 200 HCC patients of Chinese Han descent for COX-2 gene polymorphisms (-765G>C and -1195G>A) using PCR-RFLP. Data were statistically analyzed using the Kaplan-Meier method and the Cox's proportional hazard regression model. We found that patients with the COX-2 -1195AG and -1195AG + AA genotypes demonstrated significantly decreased disease-free survival (DFS) as compared with those carrying the -1195GG genotype (P < 0.05). However, the COX-2 -765G>C polymorphism was not associated with DFS (P > 0.05). Moreover, by Cox regression analysis, blood alpha fetoprotein ≤400 ng/mL before the operation and the -1195G>A polymorphism were found to be of prognostic significance (P < 0.05), while the -765G>C polymorphism was not (P > 0.05). In summary, post-operation progression of HCC is more likely to occur in patients with the -1195AG genotype and the A allele. On the other hand, the -765G>C polymorphism is not an independent influence factor of HCC prognosis.