ATPase family AAA domain-containing protein 3 (ATAD3) is a mitochondrial membrane-bound ATPase that is involved in a number of cellular processes and is linked with the progression of various types of malignancies. In primates, the ATAD3 gene cluster contains ATAD3A, ATAD3B and ATAD3C. The association between ATAD3 gene cluster expression and hepatocellular carcinoma (HCC) remains unknown. Therefore, the present study examined the prognostic significance of ATAD3 gene cluster expression in patients with HCC. Box plots of expression differences between HCC and normal liver tissues for the ATAD3 family genes were obtained from the online tool Gene Expression Profiling Interactive Analysis. Data from 360 patients with HCC in The Cancer Genome Atlas database were analyzed. Kaplan-Meier analysis and a Cox regression model were used to calculate median survival time (MST) and overall survival (OS). ATAD3A and ATAD3B expression levels were higher in HCC compared with normal liver tissues (P<0.05). However, ATAD3C expression was significantly decreased in HCC tissues compared with normal liver tissues (P<0.05). ATAD3A [P=0.017, hazard ratio (HR)=1.54, 95% confidence interval (CI)=1.08-2.20; adjusted P=0.032; adjusted HR=1.52; 95% CI=1.04-2.22] and ATAD3B (P=0.026, HR=1.49, 95% CI=1.05-2.13; adjusted P=0.031, adjusted HR=1.52, 95% CI=1.04-2.21) expression levels were significantly associated with OS. A joint-effects analysis revealed that patients with high ATAD3A and ATAD3B expression had reduced OS rates compared with patients with low ATAD3A and ATAD3B expression (P=0.007, HR=1.77, 95% CI=1.16-2.69; adjusted P=0.013, adjusted HR=1.76, 95% CI=1.13-2.75). In conclusion, ATAD3A and ATAD3B may serve as potential prognostic biomarkers for patients with HCC.