Background: Although presoaking grafts in vancomycin has been demonstrated to be effective in observational studies for anterior cruciate ligament reconstruction (ACLR) infection prevention, the economic benefit of the technique is uncertain. Purpose: To 1) determine the cost-effectiveness of vancomycin presoaking during primary ACLR to prevent postoperative joint infections and 2) to establish the break-even cost-effectiveness threshold of the technique and determine its cost-effectiveness across various international health care settings. Study Design: Economic and decision analysis; Level of evidence, 2. Methods: A Markov model was used to determine cost-effectiveness and the incremental cost-effectiveness ratio of additional vancomycin presoaking compared with intravenous antibiotic prophylaxis alone. A repeated search of the PubMed, SCOPUS, and Cochrane Central Register of Controlled Trials databases, using the same criteria as a recent meta-analysis, was completed. A repeated meta-analysis of 9 cohort studies (level 3 evidence) was completed to determine the odds ratio of infection with vancomycin presoaking compared with intravenous antibiotics alone. Estimated costs of the vancomycin technique, treatment of infection, and further surgery were sourced from local hospitals and literature. Transitional probabilities for further surgery, including revision reconstruction and primary arthroplasty, were obtained from the literature. Probabilistic sensitivity analyses and a 1-way sensitivity analysis were performed to evaluate the ACLR infection rate break-even threshold for which the vancomycin technique would be no longer cost-effective. Results: The vancomycin soaking technique provides expected cost savings of $660 (USA), A$581 (Australia), and €226 (Spain) per patient. There was an improvement in the quality-adjusted life-years of 0.007 compared with intravenous antibiotic prophylaxis alone (4.297 vs 4.290). If the infection rate is below 0.014% with intravenous antibiotics alone, the vancomycin wrap would no longer be cost-effective. Conclusion: The vancomycin presoaking technique is a highly cost-effective method to prevent postoperative septic arthritis after primary ACLR.