Central line-associated bloodstream infections (CLABSI) are a serious complication in children with intestinal failure. This study assessed the incremental costs of 4% tetrasodium ethylenediaminetetraacetic acid (EDTA) compared with taurolidine lock and heparin lock per quality-adjusted life-year (QALY) gained in children with intestinal failure from the healthcare payer and societal perspective. A Markov cohort model of a 1-year-old child with intestinal failure was simulated until the age of 17 years (time horizon), with a cycle length of 1 month. The health outcome measure was QALYs, with results expressed in terms of incremental costs and QALYs. Model parameters were obtained from published literature and institutional data. Deterministic, probabilistic, and scenario sensitivity analyses were performed. 4% Tetrasodium EDTA was dominant (more effective and less expensive) compared with taurolidine and heparin, yielding an additional 0.17 QALYs with savings of CAD$88,277 compared with heparin, and an additional 0.06 QALYs with savings of CAD$52,120 compared with taurolidine lock from the healthcare payer perspective. From the societal perspective, 4% tetrasodium EDTA resulted in savings of CAD$90,696 compared with heparin and savings of CAD$36,973 compared with taurolidine lock. This model-based analysis indicates that 4% tetrasodium EDTA can be considered the optimal strategy compared with taurolidine and heparin in terms of cost-effectiveness. The decision uncertainty can be reduced by conducting further research on the model input parameters. An expected value of perfect information analysis can identify what model input parameters would be most valuable to focus on.