BackgroundDelay in diagnosing sepsis results in potentially preventable deaths. Mainly due to their complexity or limited applicability, machine learning (ML) models to predict sepsis have not yet become part of clinical routines. For this reason, we created a ML model that only requires complete blood count (CBC) diagnostics.MethodsNon-intensive care unit (non-ICU) data from a German tertiary care centre were collected from January 2014 to December 2021. Patient age, sex, and CBC parameters (haemoglobin, platelets, mean corpuscular volume, white and red blood cells) were utilised to train a boosted random forest, which predicts sepsis with ICU admission. Two external validations were conducted using data from another German tertiary care centre and the Medical Information Mart for Intensive Care IV database (MIMIC-IV). Using the subset of laboratory orders also including procalcitonin (PCT), an analogous model was trained with PCT as an additional feature.FindingsAfter exclusion, 1,381,358 laboratory requests (2016 from sepsis cases) were available. The derived CBC model shows an area under the receiver operating characteristic (AUROC) of 0.872 (95% CI, 0.857–0.887) for predicting sepsis. External validations show AUROCs of 0.805 (95% CI, 0.787–0.824) and 0.845 (95% CI, 0.837–0.852) for MIMIC-IV. The model including PCT revealed a significantly higher performance (AUROC: 0.857; 95% CI, 0.836–0.877) than PCT alone (AUROC: 0.790; 95% CI, 0.759–0.821; p<0.001).InterpretationOur results demonstrate that routine CBC results could significantly improve diagnosis of sepsis when combined with ML. The CBC model can facilitate early sepsis prediction in non-ICU patients with high robustness in external validations. Its implementation in clinical decision support systems has strong potential to provide an essential time advantage and increase patient safety.FundingThe study was part of the AMPEL project (www.ampel.care), which is co-financed through public funds according to the budget decided by the Saxon State Parliament under the RL eHealthSax 2017/18 grant number 100331796.