e13552 Background: Sepsis is the leading cause of hospital readmission and death in the developed world. Cancer patients are at high risk due to their underlying disease and therapies. Meanwhile, antimicrobial resistance increases steadily, warranting a more careful administration of antibiotics. Predicting fever persistence 48 hours after initiation of antibiotics could help reduce antibiotic escalation and chest CT scans in patients where fever is predicted to subside within the next 24 hours. Methods: All cancer patients of the University Hospital Essen (UHE) between 1/1/2020-7/1/2023, receiving broad-spectrum i.v. antibiotics, and having persistent fever after 48 hours of first administration were extracted from UHE’s Fast Health Interoperability Resources clinical database. Vital signs, clinically important covariates, as well as lag features of vital signs and laboratory values were included. The binary target to predict was prevalence of body temperature ≥38 °C after 48-72 hours. Gradient boosting machines, a deep learning neural network, logistic regression (LR), random forest (RF) and a voting ensemble classifier were implemented. Hyperparameter tuning and model validation was performed through five-fold stratified cross validation (80/20% train/test split). Results: Analyzing 2.9 million patient records of UHE we obtained approx. 27,000 hospitalized adults with cancer. Restriction to hematology/oncology wards and intravenous broad-spectrum antibiotics resulted in 1,267 cancer patients. Of these, 264 patients had persistent fever after 48 hours, of which 111 patients had solid cancers, 66 lymphomas, and 87 other hematologic malignancies. 72 hours after antibiotic therapy 160 patients (60.2%) had persistent fever. Based on the area under the precision-recall curve (AUPRC) of 81.7%, the voting classifier model had the highest predictive performance. The model shows a sensitivity of 85%, a specificity of 63%, a Negative Predictive Value (NPV) of 75% and a Positive Predictive Value (PPV) of 73% on a cross-validated test set (Table). Conclusions: Machine learning-based algorithms can predict fever evolution and assist in clinical decision-making, potentially contributing to better patient care by preventing unnecessary antibiotics escalations and CT scans. Based on current model performance, 25% of chest CT scans could be obsolete as patients will not have persistent fever after 48 hours. Additional results will be presented at the meeting. [Table: see text]