Purpose: To investigate the expression of reticulocalbin-2 (RCN2) in human oral squamous cell carcinoma (OSCC) tissues and cell lines and its effects on the proliferation and migration of OSCC cells.Methods: Immunohistochemical (IHC) assays were performed to evaluate the expression of RCN2 in 30 histologically-confirmed OSCC patient tissues and adjacent tissues. Immunoblot assays were performed to examine the expression of RCN2 in an oral mucosal keratinocyte cell line and OSCC cell lines, while the effects of RCN2 on OSCC cell proliferation were assessed by CCK-8 and colony formation assays. The effects of RCN2 on OSCC cell motility were determined using wound closure and Transwell assays. Furthermore, the effect of RCN2 on EGFR/ERK pathway in OSCC cells was evaluated by immunoblot assay.Results: Overexpression of RCN2 occurred in OSCC tissues and cells (p < 0.01). RCN2 also increased the proliferation of OSCC cells and stimulated the motility of OSCC cells in vitro (p < 0.01). These effects occurred as a result of the regulation of EGFR/ERK signaling pathway by RCN2.Conclusion: RCN2 is a potential therapeutic target for OSCC treatment. However, further in vivo studies are required to validate these findings.