ObjectiveTo compare the susceptibility of different mice strains in different immune status to H5N1 virus,and investigate the possible mechanism. MethodsGerm free BALB/c mice,SPF BALB/c mice,SCID mice and nude mice were challenged with 50 μL 10 TCID50 H5N1 virus, then the body weight and survival were observed daily. In addition,the virus distribution in tissues,the cytokines in the lung,and pathological changes of the lung were also monitored. ResultsThe four different strains of mice could be infected by H5N1 virus successfully. The germ free mice were the lowest susceptible animals,with lowest virus replication in GF mice tissues and lowest cytokine level,including TNF-α,IL-12,MIP2,GATA3,IFN-α/β/γ,especially at the 7^th day. ConclusionsGerm free mouse is the lowest susceptible animal to H5N1 among the four mouse strains:germ-free BALB/c,SPF BALB/c,nude and SCID mice,due to low level of virus replication and low cytokine expression.