Accurately predicting red blood cell (RBC) transfusion requirements in cardiothoracic (CT) surgery could improve blood inventory management and be used as a surrogate marker for assessing hemorrhage risk preoperatively. We developed a machine learning (ML) method to predict intraoperative RBC transfusions in CT surgery. A detailed database containing time-stamped clinical variables for all CT surgeries from 5/2014-6/2019 at a single center (n = 2410) was used for model development. After random forest feature selection, surviving features were inputs for ML algorithms using five-fold cross-validation. The dataset was updated with 437 additional cases from 8/2019-8/2020 for validation. We developed and validated a hybrid ML method given the skewed nature of the dataset. Our Gaussian Process (GP) regression ML algorithm accurately predicted RBC transfusion amounts of 0 and 1-3 units (root mean square error, RMSE 0.117 and 1.705, respectively) and our GP classification ML algorithm accurately predicted 4 + RBC units transfused (area under the curve, AUC = 0.826). The final prediction is the regression result if classification predicted < 4 units transfused, or the classification result if 4 + units were predicted. We developed and validated an ML method to accurately predict intraoperative RBC transfusions in CT surgery using local data.