Objective To establish a mouse-adapted influenza H3N2 virus-infected murine model and investigatethe molecular mechanism as well as the pathogenic changes of the mouse-adapted virus strain. Methods Mouse-adaptedstrain (MA-7) was obtained by continuous passage of the A/ Aichi/2/68(H3N2) virus in mouse lungs. BALB/ c mice wereinfected intranasally to establish the model. Clinical signs, body weight loss rate, virus load in tissues and histopathologywere observed and the DNA sequences of MA-1 and wild-type stains were analyzed. Results Mice infected with A/ Aichi/2/68(H3N2) showed no obvious changes in symptoms and no virus replication was detected. However, all mice infectedwith MA-7 died within 9 days post-infection and the weight loss rate was greater than 30%. Virus replication was detected inmultiple tissues, especially the lung tissues (10^{5. 5} TCID₅₀), which caused interstitial pneumonia. Genome sequencing andalignment indicated five mutations in the HA, NA, PA and NP genes. Conclusions A mouse-adapted seasonal H3N2virus-infected murine model is successfully established, and can be used to study its pathogenesis and to evaluate drugs and vaccines. Moreover, the increased virulence of the adaptive virus strain may be related to five mutations in the virus genes.