Purpose To compare return to sport and knee function 1 year after anterior cruciate ligament (ACL) reconstruction using autografts with and without vancomycin presoaking. Methods A case–control study based on a retrospective analysis of prospective data included athletes over the age of 16 operated from 2012 to 2018 for ACL reconstruction. There were two groups of patients due to a change in treatment protocols: Group 1 « without vancomycin » before November 2016 and Group 2 « with vancomycin» after this date. In Group 2, the graft was soaked in a vancomycin solution for 10 min and then fixed into the bone tunnels. The primary evaluation criterion was the return to sport 1 year after surgery. The secondary criteria were various knee scores. The number of patients needed to perform a non-inferiority study was calculated. Results 1674 patients fulfilled the selection criteria, 1184 in Group 1 and 490 in Group 2. The series included 1112 men and 562 women, mean age 30 ± 9.7 years, 68 professional athletes, 674 competitive athletes and 932 recreational athletes. While seven patients presented with post-operative septic arthritis in Group 1, this complication was not found in Group 2. No significant difference was identified in the return to running between the two groups 1 year after surgery (75.9% vs. 76.1%, n.s.). Significantly more of the patients in Group 2 returned to their preinjury sport (p = 0.04). Knee function was comparable between the groups. Conclusion Vancomycin-soaked grafts during ACL reconstruction reduce the risk of post-operative infection of the knee without affecting the return to sport or knee function. Level of evidence III. Trial registration https://clinicaltrials.gov/, ClinicalTrials.gov Identifier: NCT02511158

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