OBJECTIVE: To explore the role of high mobility group AT-hook 2 (HMGA2) in the regulation of the cell cycle and apoptosis. METHODS: The renal carcinoma cell line ACHN was transiently transfected with small interfering RNA to knock down the expression of the gene. Cell cycle analysis was undertaken using flow cytometry. The mRNA and protein levels of HMGA2, E2F transcription factor 1 (E2F1), cyclin D1, cyclin dependent kinase 6 (CDK6), B-cell lymphoma-2 (Bcl-2), caspase-3 and caspase-9 were analysed using reverse transcription quantitative real-time polymerase chain reaction and Western blot analysis. RESULTS: The mRNA and protein levels of HMGA2 were significantly higher in renal carcinoma cell lines compared with the human renal proximal tubular epithelial cell line HKC. After gene-specific silencing, more cells entered the G/G phase, while fewer cells entered the G/M phase; and the cells exhibited early and late apoptosis. gene-specific silencing significantly reduced the mRNA and protein levels of E2F1, cyclin D1, CDK6 and Bcl-2; and increased the mRNA and protein levels of caspase-3 and caspase-9. CONCLUSION: The gene may be involved in the tumorigenesis and development of renal cancer, thus inhibiting gene expression might provide a potential therapeutic target in the future.