Antithrombin (AT) is a natural anticoagulant that is consumed during cardiac operations with cardiopulmonary bypass (CPB). This study is an observational trial aimed at identifying the factors determining the magnitude of the AT consumption during cardiac operations. Two hundred and fifty consecutive adult patients undergoing cardiac operations with CPB were admitted to the study. Preoperative and intraoperative variables were tested with respect to their role in determining AT activity at the end of the operation. At a univariate analysis, eight predictors of AT activity at the end of the operation have been identified: preoperative AT activity; age; diabetes on medication; preoperative haematocrit value; preoperative dialysis; combined operation; CPB duration; lowest temperature on CPB. A multivariate predictive model was created, and five factors remained as independent predictors of AT activity at the end of the operation: preoperative AT activity (p = 0.001); age (p = 0.015); combined operation (p = 0.014); diabetes (p = 0.013) and CPB duration (p = 0.001). On this basis, predictive tables of AT consumption have been established for different combinations of risk factors.