Background <p>Systemic inflammatory response syndrome (SIRS) is a frequent critical condition in clinical patients marked by dysregulated immune activation and high mortality. Early initiation of appropriate interventions are important for patient outcome, but molecular markers for diagnosis are not SIRS-specific.</p> Methods <p>We performed hematological analyses and health-status assessments on a transgenic disease mouse model that recapitulates elevated epidermal levels of the metalloprotease meprin α (K5Mα) reported in inflammatory skin diseases. In a cohort of intensive care patients that either developed SIRS (<i>n</i> = 19) or not (<i>n</i> = 29), we measured parameters associated with systemic inflammation and organ function as well as serum meprin α levels.</p> Results <p>K5Mα mice developed fatal SIRS characterized by hypothermia, severe weight loss, hypochromic microcytic anemia, neutrophilic leukocytosis and cytokine release syndrome. Serum concentrations of meprin α correlated with disease progression in K5Mα mice. We detected high meprin α levels in the serum of intensive care patients who developed SIRS but in none of the patients who did not develop SIRS. Serum meprin α levels significantly correlated with clinical parameters like C-reactive protein, procalcitonin and white blood cell count, but unlike all other measured inflammatory parameters allowed a clear identification of SIRS patients.</p> Conclusions <p>We propose serum meprin α levels as a potential biomarker for SIRS. However, we would like to emphasize that due to our limited cohort size subsequent larger-scale, multicentered studies are warranted to validate our findings and potentially provide more detailed insight into whether there is an association between elevated meprin α serum levels and specific causes of SIRS or dysfunction of particular organ systems.</p> Graphical Abstract <p></p>