Objective To explore the effect of regulator of chromosome condensation 2 (RCC2) on the cell proliferation in mouse models with esophageal cancer and the underlying mechanisms.Methods Esophageal tissues and primary cells from esophageal cancer mouse models and normal mice were extracted. Gene transfection was applied to regulate the expression of RCC2. The cell proliferation was detected via cell counting kit-8 (CCK-8), the expression of RCC2, sex-determining region Y-box 2 (SOX2), proliferating cell nuclear antigen (PCNA), and zinc finger protein SnaiⅠ was determined via RT-PCR and Western blot, and the targeting relationship between RCC2 and SOX2 was analyzed via luciferase assay.Results The expression of RCC2 was upregulated in the esophageal cancer tissues (P < 0.05). The cell proliferation was increased after the overexpression of RCC2 (P < 0.05), and was decreased after the inhibition of RCC2 expression (P < 0.05). Following the overexpression of RCC2, the levels of SOX2 and its target genes, PCNA and SnaiⅠ, were significantly increased (P < 0.05), while the levels of SOX2, PCNA and SnaiⅠ were significantly reduced after the inhibition of RCC2 expression (P < 0.05). Luciferase assays showed that there was a targeting relationship between RCC2 and SOX2.Conclusions RCC2 can enhance the cell proliferation in esophageal cancer mouse models by up-regulating the expression of SOX2 and its target genes, thereby further promoting the tumor formation and progression.