Aims. Failure of irrigation and debridement (I&D) for prosthetic joint infection (PJI) is influenced by numerous host, surgical, and pathogen-related factors. We aimed to develop and validate a practical, easy-to-use tool based on machine learning that may accurately predict outcome following I&D surgery taking into account the influence of numerous factors. Methods. This was an international, multicentre retrospective study of 1,174 revision total hip (THA) and knee arthroplasties (TKA) undergoing I&D for PJI between January 2005 and December 2017. PJI was defined using the Musculoskeletal Infection Society (MSIS) criteria. A total of 52 variables including demographics, comorbidities, and clinical and laboratory findings were evaluated using random forest machine learning analysis. The algorithm was then verified through cross-validation. Results. Of the 1,174 patients that were included in the study, 405 patients (34.5%) failed treatment. Using random forest analysis, an algorithm that provides the probability for failure for each specific patient was created. By order of importance, the ten most important variables associated with failure of I&D were serum CRP levels, positive blood cultures, indication for index arthroplasty other than osteoarthritis, not exchanging the modular components, use of immunosuppressive medication, late acute (haematogenous) infections, methicillin-resistant Staphylococcus aureus infection, overlying skin infection, polymicrobial infection, and older age. The algorithm had good discriminatory capability (area under the curve = 0.74). Cross-validation showed similar probabilities comparing predicted and observed failures indicating high accuracy of the model. Conclusion. This is the first study in the orthopaedic literature to use machine learning as a tool for predicting outcomes following I&D surgery. The developed algorithm provides the medical profession with a tool that can be employed in clinical decision-making and improve patient care. Future studies should aid in further validating this tool on additional cohorts. Cite this article: Bone Joint J 2020;102-B(7 Supple B):11–19