Background: Vancomycin soaking of the graft during arthroscopic anterior cruciate ligament reconstruction has been shown to be effective in reducing the rate of postoperative infection. Purpose/Hypothesis: The present study aimed to (1) analyze the effect of vancomycin-soaked grafts during arthroscopic anatomic reconstruction of the anterior talofibular ligament (ATFL) and the calcaneofibular ligament (CFL) on the incidence of infection and (2) evaluate the influence of infection on functional outcomes and identify the risk factors of infection. It was hypothesized that vancomycin soaking of the graft would reduce the postoperative infection rate. Study Design: Cohort study; Level of evidence, 3. Methods: Consecutive patients at 2 centers who underwent ATFL/CFL reconstruction between December 2011 and July 2022 were included. All patients had undergone anterolateral arthroscopic debridement of the ankle and anatomic ATFL/CFL reconstruction with a gracilis tendon autograft. Vancomycin soaking of the graft was begun in both centers in January 2021. Complications, functional scores, return to sports (RTS) rates, and the level of return were compared between patients with and without vancomycin-soaked grafts and between patients with and without infection. Results: Overall, 182 patients (48% men; mean age, 34 ± 11.9 years) were included, with a mean follow-up of 23 ± 16.1 months. The rate of postoperative infection was significantly lower in the group with vancomycin soaking versus without (0/92 [0%] vs 8/90 [8.9%]; P = .001). At the final follow-up, there were 26 complications (14.3%): 8 infections, 6 recurrent tears, and 12 peripheral neuropathies. The infections developed after a mean of 17 ± 11 days. The functional scores were excellent at the final follow-up (American Orthopaedic Foot and Ankle Society [AOFAS] Ankle-Hindfoot Score, 86.5 ± 18.7; Karlsson score, 85 ± 18.3). Patients with infection had significantly decreased AOFAS scores (52.8 ± 27.6 vs 83.3 ± 21.5; P = .003), Karlsson scores (57 ± 27.7 vs 83.6 ± 20; P = .006), and RTS rates (25% vs 77%; P = .005) versus patients without infection. Conclusion: Vancomycin-soaked grafts for arthroscopic anatomic ATFL/CFL reconstruction decreased the rate of postoperative infection. Infection led to a deterioration in results. Vancomycin-soaking of the graft did not have a negative effect on functional results.