Plasma samples and clinical data were prospectively collected from 54 patients with severe CAP requiring ICU admission. Seventeen healthy control subjects were included for comparison. Plasma kallistatin, kallikrein, and other biomarkers of inflammation (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta, IL-6, IL-8, C-reactive protein [CRP]) and anti-coagulation (protein C, anti-thrombin III) were measured on days 1 and 4 of ICU admission. Comparison between survivors (n = 41) and non-survivors (n = 13) was performed.Plasma kallistatin was significantly consumed in severe CAP patients compared with healthy individuals. Lower day 1 kallistatin levels showed a strong trend toward increased mortality (P = 0.018) and higher day 1 CURB-65 scores (P = 0.004). Plasma kallistatin levels on day 1 of ICU admission were significantly decreased in patients who developed septic shock (P = 0.017) and who had acute respiratory distress syndrome (P = 0.044). In addition, kallistatin levels were positively correlated with anti-thrombin III and protein C and inversely correlated with IL-1beta, IL-6 and CRP levels. In a multivariate logistic regression analysis, higher day 1 CURB-65 scores were independent predictors of mortality (odds ratio = 29.9; P = 0.009). Also, higher day 1 kallistatin levels were independently associated with a decreased risk of death (odds ratio = 0.1) with a nearly significant statistical difference (P = 0.056). Furthermore, we found that a cutoff level of 6.5 mug/mL of day 1 kallistatin determined by receiver operating characteristic curves could be used to distinguish between patients who survived in 60 days and those who did not.These results suggest that kallistatin may serve as a novel marker for severe CAP prognosis, and may be involved in the pathogenesis of CAP through anti-inflammatory and anti-coagulation effects.