Cullin 4A (CUL4A) is the major component of cullin-RING-based E3 ubiquitin-protein ligase complexes, which regulate the ubiquitination of target proteins. The overexpression of CUL4A has been associated with the development and progression of various cancer types. However, a detailed understanding of the role of CUL4A in human liver cancer has not been determined by previous studies. In the present study, the association between human liver cancer and CUL4A expression was investigated. The expression of CUL4A in liver cancer tissues and paracancerous tissues of patients was investigated by reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemical staining. Overexpression and knockdown of CUL4A were induced with an overexpression vector and small interfering RNA transfection, respectively, in human liver cancer cell lines, and the effects on cell proliferation were analyzed by a Cell Counting Kit-8 assay to investigate the role of CUL4A in human liver cancer. Cell migration, invasion, apoptosis and the cell cycle were also analyzed following transfection. The results of the present study revealed that the mRNA and protein expression of CUL4A was increased in the liver cancer tissues compared with the paracancerous tissues of 3 patients. Additionally, the results demonstrated that downregulation of CUL4A expression inhibited cell proliferation, migration and invasion, and increased the percentage of cell apoptosis, in HEPG2 and MHCC97-H cells, while CUL4A overexpression led to the opposite effects. Therefore, the results of the current study indicated that CUL4A may serve an important role in the development and progression of human liver cancer, and highlights the potential of CUL4A as a novel target in the diagnosis and treatment of human liver cancer and potentially other cancer types.