Every day, the immune system makes decisions to differentiate harmful and inert stimuli, which allows protection against pathogens and prevents unnecessary or uncontrolled inflammation. Perturbations to the innate immune system can lead to autoinflammatory disorders such as Familial Mediterranean Fever (FMF), which is an inherited disorder characterized by unprovoked episodes of inflammation and fever. The genetic abnormality underlying FMF disorder is mutations in the gene MEFV (Mediterranean Fever), which encodes the protein Pyrin. Previous research indicates that Pyrin alters function of the inflammasome multiprotein complex that mediates post-translational IL-1 family cytokine processing. This work has led to disparate conclusions about the function of Pyrin. Interpretation of these results is ambiguous, in part, because mutations within the Pyrin protein are not defined as gain or loss of function. Previous research also indicates that the expression of MEFV is abundant in neutrophils, and that neutrophils from FMF patients display altered immune function and survival in comparison to neutrophils from healthy donors. However, there is no direct evidence that mutations in Pyrin affect neutrophil cell processes. We postulated that mice lacking Pyrin (Mefv-/-) would allow us to clarify the function of Pyrin in the regulation of the immune response and FMF pathophysiology. Characterization of naïve Mefv-/- mice revealed no deficits in immune cell development or distribution and no indication of unprovoked inflammation. In response to immune challenge in vitro, IL-1β cytokine levels were increased by the absence of Pyrin. However, neutrophil recruitment and survival were not affected by the loss of Pyrin. In vivo models of peritonitis demonstrated that Mefv-/- mice generate a normal hypothermic response and recruit and retain inflammatory cells normally. No difference in the physiological outcome of immune challenge was detected. These studies indicate that Pyrin negatively regulates the immune response by altering IL-1β secretion. Since IL-1β is at least in part responsible for FMF-associated inflammation, our findings support a model in which loss-of-function mutations in Pyrin can cause FMF.