<jats:title>Abstract</jats:title> <jats:p>MKP-1 is a critical negative regulator of p38 and JNK MAP kinases. While loss of Mkp-1 function enhances cytokine production after bacterial challenge, little is known about the role of Mkp-1 in the innate immune response to viral infections. In this study we examined the role of Mkp-1 in the pulmonary immune response during influenza infection in mice. Mkp-1+/+ and Mkp-1-/- mice were intranasally inoculated with 1,000 plaque-forming units of the mouse-adapted H1N1 A/WSN/33 strain of influenza. Mice were monitored up to 6 days post inoculation and evaluated for altered host physiology, viral replication, and host immune response. Compared to Mkp-1+/+ animals, Mkp-1-/- mice exhibited accelerated weight loss and hypothermia. cDNA array analysis indicated that over 50 immune response-related genes were more robustly expressed in the lungs of Mkp-1-/- mice than in the Mkp-1+/+ mice upon influenza infection. The levels of IL-6, IL-10, and IFN-β were also higher in bronchoalveolar lavage fluid from Mkp-1-/- mice. Mechanistically, p38 and JNK activation was prolonged in Mkp-1 deficient cells treated with agents mimicking viral RNA. Together, these data support the model that Mkp-1 plays an important role in the feedback control of p38 and JNK, thus limiting harmful innate immune response and preventing severe clinical disease during pulmonary influenza infection.</jats:p>