Influenza B viruses (IBV) primarily infect humans, causing seasonal epidemics. The absence of an animal reservoir limits pandemic concern, but IBV infections may cause severe respiratory disease, predominantly in young children and the elderly. The IBV disease burden is largely controlled by seasonal influenza vaccination; however, immunity due to vaccination is sometimes incomplete, a feature linked to antigenic mismatches. Thus, understanding the features that contribute to disease pathogenesis is important, particularly immune-mediated versus virus-mediated outcomes. Unexpectedly, C57BL/6 (B6) mice intranasally infected with a low multiplicity of infection of B/Florida/04/2006 developed substantial morbidity and mortality. To address the cause, B6 mice were treated daily with dexamethasone to dampen the immune and pro-inflammatory response to IBV infection, allowing the determination of whether the responses were immune- and/or virus-associated. As expected, dexamethasone (DEX)-treated mice had a lower pro-inflammatory response and reduced lung pathology despite the presence of high viral lung titers, but mortality was comparable to PBS-treated mice, indicating that mortality may be linked to lung virus replication. The results showed that the immune response to IBV is the major cause of morbidity, mortality, lung pathology, and viral clearance. Importantly, the results suggest that a robust lung CTL response and associated leukocyte influx contribute to disease.