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Septic shock is commonly associated with hemostatic abnormalities. The endothelium-activated serine protease activated protein C (APC) plays a pivotal role in limiting coagulation and possesses anti-apoptotic and anti-inflammatory properties. We hypothesized that APC levels correlate with established coagulation parameters and provide prognostic information in patients with septic shock.We conducted a prospective, observational cohort study in patients with septic shock. APC was measured on admission (day 0) and on days 1, 3, and 6 by a clinically applicable oligonucleotide (aptamer)-based enzyme-capture assay (OECA). The primary endpoint was defined as sepsis-associated 30-day mortality. Furthermore, we analyzed the correlation of APC levels with established coagulation markers.48 consecutive patients admitted with septic shock were included (mortality 39.6%). APC levels were elevated upon admission (0.59 ng/ml, IQR 0.26–0.97) and showed a strong correlation with established markers of coagulation and lactate. Multivariable logistic regression identified APC (OR 4.3, 95% CI 1.1–17.8, p = 0.04) and lactate levels (OR 7.0, 95% CI 4.1–18.2, p = 0.04) as independent predictors of 30-day mortality.APC levels are increased in patients with septic shock and are correlated with established markers of coagulation. Elevated APC levels on admission are an independent predictor of mortality.Levels of endogenous APC are elevated during early septic shock.Endogenous APC is an independent predictor of mortality in septic shock.Lactate and APC levels demonstrate a significant correlation.Tissue hypoperfusion is associated with the activation of the protein C/APC system.