AIM: To evaluate the efficacy of different treatment strategies for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) and investigate factors influencing prognosis. METHODS: One hundred and seventy-nine HCC patients with macroscopic PVTT were enrolled in this study. They were divided into four groups and underwent different treatments: conservative treatment group (n = 18), chemotherapy group (n = 53), surgical resection group (n = 24) and surgical resection with postoperative chemotherapy group (n = 84). Survival rates of the patients were analyzed by the Kaplan-Meier method. A log-rank analysis was performed to identify group differences. Cox’s proportional hazards model was used to analyze variables associated with survival. RESULTS: The mean survival periods of the patients in four groups were 3.6, 7.3,10.1, and 15.1 mo respectively. There were significant differences in the survival rates among the groups. The survival rates at 0.5-, 1-, 2-, and 3-year in surgical resection with postoperative chemotherapy group were 55.8%, 39.3%, 30.4%, and 15.6% respectively, which were significantly higher than those of other groups (p<0.001). Multivariate analysis revealed that the strategy of treatment (P<0.001) and the number of chemotherapy cycles (P = 0.012) were independent survival predictors for patients with HCC and PVTT. CONCLUSION: Surgical resection of HCC and PVTT combined with postoperative chemotherapy or chemoembolization is the most effective therapeutic strategy for the patients who can tolerate operation. Multiple chemotherapeutic courses should be given postoperatively to the patients with good hepatic function reserve.