BACKGROUND Community-acquired pneumonia (CAP) is a common disease with significant morbidity and mortality. Interferon regulatory factor 5 (IRF5), which induces type I interferons (IFNs) and cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-10, and interferon gamma-induced protein (IP)10, is a key transcription factor involved in controlling the expression of proinflammatory cytokines and responses to infection. Here, we carefully investigated the role of IRF5 in regulating immune responses to CAP. MATERIAL AND METHODS QRT-PCR was used to detect the mRNA levels of IRF5, IL-6, IL-10, IP10, TNF-α, and IFN-α in the peripheral blood of 71 CAP patients and 31 healthy controls, as well as in the bronchoalveolar lavage cells of 20 patients with CAP and 23 patients with lung cancer (using samples from the unaffected lung). Flow cytometry was performed to detect the protein level of IRF5, and a CBA flex set was used to detect the levels of these cytokines in the volunteers. RESULTS The expression levels of IRF5 and its related cytokines were significantly increased in CAP patients compared with the controls. Additionally, IRF5, IL-6, IL-10, and IP10 levels were found to be related with the severity of CAP. Furthermore, the levels of IRF5 and IFN-a increased significantly in the early phase of pneumonia caused by influenza virus infection. CONCLUSIONS IRF5 and its related inflammatory cytokines are associated with the severity, prognosis, and causative pathogen of CAP patients. This finding may provide new drug targets for the prevention and treatment of severe pneumonia caused by influenza virus.