One of the immunosuppressive responses when hepatocellular carcinoma (HCC) develops in mammals is defective proliferation in the spleen. The objective of this study was to investigate the protective effect of the Styrax japonica Siebold et al. Zuccarini (SJSZ) glycoprotein on the proliferation of splenocytes induced by diethlynitrosamine (DEN). To assess whether the SJSZ glycoprotein modulates splenocyte proliferation, Balb/c mice were injected intraperitoneally with DEN (50 mg/kg, BW) for 7 weeks. After 7 weeks, the mice were sacrificed, and spleens were isolated. We evaluated [3H]-thymidine incorporation, extracellular signal-regulated kinase (ERK), cell cycle-related factors [p53, p21, p27, cyclin D1/cyclin dependent kinase (CDK) 4], proliferating cell nuclear antigen and interferon (IFN)-γ using radiation activity, immunoblot analysis, and the reverse transcription-polymerase chain reaction. The results revealed that the SJSZ glycoprotein (10 mg/kg, BW) increased [3H]-thymidine incorporation, ERK phosphorylation, expression levels of cyclin D1/cyclin dependent kinase 4, and IFN-γ. However, the SJSZ glycoprotein decreased levels of p53, p21, and p27. Taken together, these results suggest that the SJSZ glycoprotein inhibited defective splenocyte proliferation induced by DEN. J. Cell. Biochem. 114: 808–815, 2013. © 2012 Wiley Periodicals, Inc.