To investigate whether MHC classes I and II molecules were involved in the host innate immune response to H5N6 influenza virus infection, we examined their expression levels in the lung, brain, spleen, and bursa of Fabricius in chickens at 3 DPI. As illustrated in Figures 5A,B, MHC classes I and II molecule expression levels were upregulated in the brain, spleen, and bursa of Fabricius when infected by both viruses. In the lung, in contrast to the mock-infected control, the expression level of the MHC class I molecule was remarkably downregulated (0.063- and 0.20-fold, respectively, p < 0.05); however, that of the MHC class II molecule was significantly upregulated when induced by SW8 and ZH283 (12.83- and 99.08-fold, respectively, p < 0.05). Those results demonstrated that MHC classes I and II molecules could play a significant role in the course of host innate immune response to H5N6 influenza virus infection in chickens.