Abstract Background: Characterizing the evolution of protein C concentrations in critically ill patients may help in identifying high risk groups and potential therapeutic targets. The authors investigated the time courses of protein C concentrations and their relation to the presence of sepsis, organ dysfunction/failure, and outcome. Methods: This observational cohort study, in a university hospital surgical intensive care unit (ICU), included 312 consecutive patients with an estimated ICU length of stay more than 48 h. Plasma protein C concentrations and parameters of organ dysfunction were measured daily until discharge or death. Results: Protein C concentrations were below the lower limit of normal in 50.6% of patients (n = 158) on admission and decreased to a nadir within 3–4 days after admission before almost normalizing by 2 weeks thereafter, irrespective of the presence of sepsis, sex, source and type of admission, and type of surgery. The minimum protein C concentration was lower in patients with severe sepsis/septic shock (n = 54) than in those with sepsis (n = 63) and those who never had sepsis (n = 195), and was negatively correlated to the maximum Sequential Organ Failure Assessment score (R2 = 0.345, P < 0.001). Protein C levels were lower in nonsurvivors (n = 46; 14.7%) than in survivors, especially in the first 4 days after admission. In a multivariable analysis with ICU mortality as the dependent variable, a minimum protein C concentration less than 45% was an independent risk factor for ICU death. Conclusions: In critically ill surgical patients, protein C concentrations were generally low, associated with organ dysfunction/failure, and independently associated with a higher risk of ICU mortality.