Mice infected with Dhori virus (DHOV) develop a fulminant, systemic, and uniformly fatal illness that has many of the clinical and pathologic findings seen in H5N1 influenza A virus infection. However, the role of host’s immune response in DHOV infection remains unclear. In this study, the concentrations of 23 inflammatory cytokines and chemokines were measured in the liver, lungs, and sera of mice during the course of DHOV infection. Liver function, level of viremia, and hematologic response were also monitored. Infected animals exhibited significant leucopenia and lymphopenia, which directly correlated with the disease progression. High yields of infectious virus along with strikingly elevated expression of various inflammatory mediators, including tumor necrosis factor (TNF)-α, inter-leukin (IL)-1, IL-6, IL-10, macrophage inflammatory protein (MIP)-1α, manocyte chemoattractant protein (MCP)-1, and interferon (IFN)- α, indicate that these responses play an important role in the observed disease and pathology. The overall clinical, pathologic, and immunologic responses of ICR mice to DHOV infection closely resemble those described for highly virulent influenza A virus infection in humans, thereby offering a realistic, safe, and alternative animal model for studying the pathogenesis and treatment of highly pathogenic avian influenza virus.