To investigate epidermal growth factor receptor (EGFR) and thymidylate synthase (TS) expression in primary liver cancer, and analyze its clinicopathological features and prognostic significance. Immunohistochemistry was performed using EnVision method to detect EGFR and TS expression in 41 cases of liver cancer. Correlation coefficient between EGFR and TS was calculated by Spearman method. Fisher's exact probability method or (2) test was used to analyze the clinicopathological features of EGFR and TS. Kaplan-Meier method was used to calculate the survival rate of patients in conjunction with the log-rank test.COX proportional hazard regression model was used to analyze the prognostic factors of patients. ROC curve was used to analyze the predictive accuracy of EGFR and TS for prognosis. The positive rates of EGFR and TS in liver cancer tissues were 34.15% and 39.02%, respectively. There was a positive correlation between EGFR and TS expressions, and the difference was statistically significant ( < 0.05). EGFR was associated with tumor size and tissue differentiation ( < 0.05) in HCC patients, whereas TS was associated with tissue differentiation ( < 0.05). There was no significant difference in prognostic effect of EGFR on survival rate ( > 0.05). TS prognostic effect on survival rate was statistically significant ( < 0.05). HR of EGFR was 0.210 with 95% , 0.052-0.852, = 0.029; indicating that the risk of death in patients with negative EGFR was 0.210 times higher than that in patients with positive EGFR. HR of TS was 2.496, with 95% , 1.325-4.701, = 0.005, indicating that the risk of death increased by 2.496 times with the same level of EGFR. The area under the EGFR curve was 0.553 and its approximate reference confidence interval was 95% (0.355, 0.751), indicating that EGFR was a risk factor for death and the area under the TS curve was 0.695, and its approximate reference confidence interval was 95% (0.513, 0.878), indicating that TS was a risk factor for death. EGFR and TS were equally expressed in primary liver cancer, and EGFR and TS expressions were positively correlated. EGFR and TS had an effect on the degree of tissue differentiation in patients with liver cancer. EGFR and TS were risk factors for prognosis, and TS may assist EGFR.