Objective To analyze and compare the pathological changes of lung tissue in mice infected with the novel H7N9 influenza virus and 2009 pandemic H1N1 influenza virus, respectively, and to preliminarily study the mechanisms of acute lung injury induced by those virus infection. Methods SPF 6-week old BALB/c mice (body weight 18-20 g, male :female=1:1) (n=3 in each subgroup) were intranasally infected with H7N9 virus and H1N1 virus, respectively. The behavior and survival time of mice after virus infection were observed and the survival rates were analyzed. The heart, liver, spleen, lung, kidney, intestines, and brain were collected at indicated time points for histopathological examination using H&E staining. The distribution of virus antigen was detected by immunohistochemistry. The neutrophil infiltration was also observed. The correlation of lung injury with virus replication and host immune responses was analyzed. Results The lung and spleen injury of mice infected with H7N9 virus was slighter and their survival rate (100%) was higher than those of mice infected with H1N1 virus. The damages of the lung and spleen in H1N1virus-infected mice were more severe than that in H7N9 virus-infected mice, and all the 10 mice in this group died within 9 days after virus inoculation. The distributions of both the virus antigens were mainly in the bronchial epithelial cells, a few stromal cells and alveolar epithelial cells. The levels of virus replication in the two groups were not significantly different. There were more intense neutrophil infiltration in the lung and inflammatory response in the H1N1 virus-infected mice than those in the H7N9 virus-infected mice. Conclusions There are some differences of the pathological characteristics and extent of lung injury in the mice infected with H7N9 virus and H1N1 virus, respectively. The virus replication is a precipitating factor but not the decisive factor of the lung injury, and there is a close relationship between the host immune responses and acute lung injury.