Objective To investigate the molecular mechanism of tumor protein 63 with truncated transactivation domain (ΔNp63) in regulating the proliferation and migration of esophageal squamous cell carcinoma (ESCC) cells.Methods With ECA109 cells as a model, ΔNp63 was overexpressed in cells by transgene mediated with lentivirus. The expression level of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) was detected by quantitative polymerase chain reaction and Western blotting, and the binding of ΔNp63 and the 5'-untranslated region (5'-UTR) of HMGCR was detected by chromatin immunoprecipitation (ChIP) and luciferase activity reporter assay. ΔNp63 was overexpressed in cells and the expression of HMGCR was inhibited by RNA interference. Cell proliferation was detected by cell counting kit 8 (CCK-8), apoptosis was detected by flow cytometry, and cell migration was detected by Transwell chamber culture.Results The mRNA and protein expression levels of HMGCR were increased after overexpressing ΔNp63 in ECA109 cells (both P < 0.01). The results of the ChIP and luciferase activity reporter assay showed that the ΔNp63 recognition site was located in the -728 to -747 bp region of the HMGCR promoter. The cell proliferation ability of the group overexpressing ΔNp63 and inhibiting HMGCR expression was significantly lower than that of the group overexpressing ΔNp63 alone at 24, 48 and 72 h (all P < 0.05); the level of apoptosis was (26.9±1.9)%, which was significantly higher than that of the group overexpressing ΔNP63 alone ([16.6±1.5]%, P < 0.01); meanwhile, the cell migration rate was significantly lower than that of the group overexpressing ΔNp63 alone ([33.4±3.1]% vs[52.2±2.6]%, P < 0.01).Conclusion ΔNp63 can promote the proliferation and migration of ESCC cells by up-regulating the transcriptional expression of HMGCR.