ObjectiveTo investigate the expression levels of forkhead box A2 (FOXA2) and forkhead box J2 (FOXJ2) in hepatocellular carcinoma (HCC) tissue and the association of FOXA2 and FOXJ2 with HCC. MethodsClinical data and pathological tissue samples were collected from 54 patients with pathologically confirmed HCC in The First Affiliated Hospital of Henan University of Traditional Chinese Medicine from January 2014 to July 2019. The immunohistochemical SP method was used to measure the protein expression levels of FOXA2 and FOXJ2 in HCC tissue, and their association with HCC-related clinicopathological features and patient prognosis was analyzed. The chi-square test and the adjusted chi-square test were used for comparison of categorical data; a Spearman correlation analysis was performed to investigate the correlation between the expression of FOXA2 and FOXJ2; the Kaplan-Meier method was used for survival analysis; Image-Pro Plus was used to perform the semi-quantitative analysis of the expression of FOXA2 and FOXJ2; the Wilcoxon rank-sum test was used for comparison between groups. ResultsThe positive rates of the protein expression of FOXA2 and FOXJ2 in HCC tissue were 70.37% (38/54) and 75.92% (41/54), respectively, and there was a significant positive correlation between the expression levels of FOXA2 and FOXJ2 (rs=0.648, P＜0.001). In both negative and positive groups, the expression level of FOXA2 was associated with tumor diameter, degree of tumor differentiation, number of tumors, and alpha-fetoprotein (χ2=5.440, 4.113, 4.352, and 3.865, P=0.020, 0.043, 0037, and 0.049), and the expression level of FOXJ2 was associated with the degree of tumor differentiation (χ2=9.267, P=0.002). The group with positive expression of FOXA2 and FOXJ2 had a significantly higher cumulative survival rate than the group with negative expression of FOXA2 and FOXJ2 (P＜0.01). ConclusionThe expression levels of FOXA2 and FOXJ2 are associated with the development, progression, and prognosis of HCC, and they have a synergistic effect in the development and progression of HCC.