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Background: Few studies on outcomes after anterior cruciate ligament (ACL) reconstruction (ACLR) have provided insight into the very long-term effects of this procedure. Purpose: To systematically review the outcomes, failure rate, incidence, and predictors of osteoarthritis (OA) for different ACLR techniques at a minimum 20-year follow-up. Study Design: Systematic review; Level of evidence, 4. Methods: A search of the PubMed, SCOPUS, and Cochrane databases was performed on June 2020 for studies of patients who underwent ACLR and had a minimum follow-up of 20 years. We extracted data on patient and surgical characteristics, patient-reported outcomes (Lysholm score, subjective International Knee Documentation Committee [IKDC] score, Knee injury and Osteoarthritis Outcome Score [KOOS], and Tegner score), clinical outcomes (IKDC grade, pivot shift, Lachman, and KT-1000 laxity), degree of OA (Kellgren-Lawrence, Ahlbäck, and IKDC OA grading), revisions, and failures. Relative risk (RR) of OA between the operated and contralateral knees was calculated as well as the pooled rate of revisions, failures, and conversion to total knee arthroplasty (TKA). Results: Included were 16 studies (N = 1771 patients; mean age, 24.8 years; mean follow-up, 22.7 years); 80% of the patients underwent single-bundle bone–patellar tendon–bone (BPTB) reconstruction. The average Lysholm (89.3), IKDC (78.6), and KOOS subscale scores were considered satisfactory. Overall, 33% of patients had “abnormal” or “severely abnormal” objective IKDC grade, 6.7% had KT-1000 laxity difference of ≥5 mm, 9.4% had Lachman ≥2+, and 6.4% had pivot shift ≥2+. Signs of OA were reported in 73.3% of patients, whereas severe OA was reported in 12.8%. The operated knee had a relative OA risk of 2.8 ( P < .001) versus the contralateral knee. Identified risk factors for long-term OA were male sex, older age at surgery, delayed ACLR, meniscal or cartilage injuries, BPTB autograft, lateral plasty, nonideal tunnel placement, residual laxity, higher postoperative activity, and postoperative range of motion deficits. Overall, 7.9% of patients underwent revision, and 13.4% of ACLRs were considered failures. TKA was performed in 1.1% of patients. Conclusion: Most patients had satisfactory subjective outcomes 20 years after ACLR; however, abnormal anteroposterior or rotatory laxity was found in nearly 10% of cases. The presence of radiographic OA was high (RR 2.8 vs uninjured knee), especially in patients with concomitant meniscal or cartilage injuries, older age, and delayed surgery; however, severe OA was present in only 12.8% of cases, and TKA was required in only 1.1%.