Objective To clarify relationship between signal heterogeneity on hepatobiliary phase of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced MRI and prognosis of hepatocellular carcinoma (HCC). Methods From January 2014 to January 2017 in the First Affiliated Hospital of Chongqing Medical University, a total of 77 patients with the pathologically proved HCC underwent Gd-EOB-DTPA-enhanced MRI prior to surgery were included in this study. On the basis of the signal heterogeneity in the hepatobiliary phase, the included patients were designed to homogeneous hypointensity group and heterogeneous hyperintensity group. The disease-free survival time were compared between the 2 groups and it’s influencing factors were analyzed. Results Seventy-seven patients with HCC were included, including 45 cases of homogeneous hypointensity and 32 cases of heterogeneous hyperintensity. There were no significant differences in the age, gender, etiology, liver function, alpha-fetoprotein, differentiated degree, Child-Pugh grade, lesion diameter, lesion border, and number of lesions between the 2 groups (P>0.05). However, the HCC patients with heterogeneous hyperintensity had a later BCLC staging (P=0.001). The disease-free survival time of the patients with homogeneous hypointensity and heterogeneous hyperintensity was (17.0±9.8) months and (12.4±10.4)months, respectively. The Kaplan-Meier survival curve showed that the disease-free survival time in the patients with homogeneous hypointensity was significantly better than that in the patients with heterogeneous hyperintensity (P=0.020). The results of univariate analysis showed that the other confounding factors had no effect on the disease-free survival time of patients with hepatocellular carcinoma (P>0.05) except for the signal of hepatobiliary phase (P<0.05). Furthermore, the hepatobiliary phase signal, BCLC stage, and degree of differentiation, which might be clinically considered as potentially influencing for the prognosis of patients with HCC, were included in the Cox multivariate proportional hazard regression model and found that the heterogeneous hyperintensity was still the risk factor of the disease-free survival rate in patients with HCC (P=0.047). Conclusion Signal heterogeneity on hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI is related to prognosis of patients with HCC, heterogeneous hyperintensity may indicate a lower disease-free survival rate.