Context <p>Children with empyema thoracis often respond to medical management, but some do not, and require surgical intervention. Prediction of failure of medical management will help to guide further management and plan surgical intervention.</p> Objective <p>To systematically review literature for clinical, radiological, laboratory, or microbiological predictors, associated with failure of medical management or the need for surgery in children with empyema thoracis.</p> Evidence Acquisition <p>A systematic search was conducted in seven databases (PubMed, Embase, Cochrane Library, Scopus, Web of Science, ProQuest, and Open Grey) and four trial registries. Observational studies exploring predictors of treatment failure in empyema thoracis were eligible. Two reviewers independently screened the studies, extracted the data, and assessed the risk of bias. Data were analyzed in accordance with the review protocol.</p> Results <p>Amongst 12,311 citations identified, seven studies were included. One study identified three statistically significant predictors of medical treatment failure, viz. immediate ICU admission: OR (95%CI) 1.95 (1.18, 3.22); absence of complex septations on ultrasonography: 1.72 (1.21, 2.47); and positive blood culture: 2.8 (1.54, 5.07). Another study reported that “continuing pus discharge for ≥ 10&#xa0;days after chest tube insertion” and “persistence of loculations on ultrasonography or CT scan despite fibrinolytic therapy” prompted surgical intervention. The presence of fever was identified as a significant predictor, although its duration and grade were not reported. The evidence had very low overall certainty, being limited by small, single-center, retrospective studies with heterogeneous designs, population, and outcome definitions, limiting generalizability.</p> Conclusions <p>Current evidence did not identify any clinically meaningful predictors of the failure of medical management (or need for surgery) in children with empyema thoracis.</p>