Objective To explore the feasibility of establishing a tree shrew model of Human Noroviruses (HuNoVs) infection by inoculation with HuNoVs. Methods Three groups of 6-month-old tree shrews (five in each group) were treated with GII.4 type HuNoVs 2010, Sydney strains or an equal dose of PBS (control). Physical signs and diarrhea were observed for 7 days after HuNoVs challenge. HuNoVs RNA was detected by RT-PCR using stool samples collected every 24 h, and then the tree shrews were sacrificed to collect the small intestinal tissues. HE staining was used to observe pathological changes. The presence of HuNoVs antigen was tested by immunohistochemistry (IHC), and the saliva from tree shrews was analyzed for histoblood group antigen(HBGAs)by ELISA. Results No obvious infection symptoms or diarrhea were observed in the tree shrews after HuNoVs challenge. No HuNoVs RNA was detected in stool specimens, and no HuNoVs antigen was detected in the small intestine. No pathological changes were observed. HBGAs antigen was negative in the saliva of tree shrews. Conclusions Tree shrews are not susceptible to HuNoVs possibly because of the lack of HBGAs expression and common breeding conditions. The small animal model of tree shrews infected with HuNoVs remains to be further explored.