BACKGROUND Ciprofloxacin is a widely used antibiotic that has lost efficiency due to extensive resistance. We developed machine learning (ML) models that predict the probability of ciprofloxacin resistance in hospitalized patients. METHODS Data were collected from electronic records of hospitalized patients with positive bacterial cultures, during 2016-2019. Susceptibility results to ciprofloxacin (n = 10,053 cultures) were obtained for Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Pseudomonas aeruginosa, Proteus mirabilis and Staphylococcus aureus. An ensemble model, combining several base models, was developed to predict ciprofloxacin resistant cultures, either with (gnostic) or without (agnostic) information on the infecting bacterial species. RESULTS The ensemble models' predictions are well-calibrated, and yield ROC-AUCs (area under the receiver operating characteristic curve) of 0.737 (95%CI 0.715-0.758) and 0.837 (95%CI 0.821-0.854) on independent test-sets for the agnostic and gnostic datasets, respectively. Shapley additive explanations analysis identifies that influential variables are related to resistance of previous infections, where patients arrived from (hospital, nursing home, etc.), and recent resistance frequencies in the hospital. A decision curve analysis reveals that implementing our models can be beneficial in a wide range of cost-benefits considerations of ciprofloxacin administration. CONCLUSIONS This study develops ML models to predict ciprofloxacin resistance in hospitalized patients. The models achieve high predictive ability, are well calibrated, have substantial net-benefit across a wide range of conditions, and rely on predictors consistent with the literature. This is a further step on the way to inclusion of ML decision support systems into clinical practice.