[Objective] To investigate the role of blood dissemination in the invasion of the central nervous system by the highly pathogenic H5N1 influenza viruses. [Methods] Three H5N1 strains were intranasally inoculated into BALB/c mice to study the replication and pathogenic kinetics of the viruses in lung, brain, and blood. Infection of the brain vascular endothelial cells and nerve tissue around the blood vessels by the virus was investigated by immunohistochemistry and immunofluorescence staining techniques. [Results] Virus replicated efficiently in lungs, leading to viremia quickly after inoculation. At 6 d post inoculation, both the viral titre in lungs and the detection rate of viremia peaked; concomitantly, the viral NP (Nuclear protein) protein began to be detectable in the central nervous system. Viral NP proteins were observed in the brain vascular endothelial cells and in the neurons and astrocytes around blood vessels. [Conclusion] Blood dissemination could be one of the pathways through which the highly pathogenic H5N1 influenza invades the central nervous system.