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Background: The long-term prognosis and risk factors for quality of life and disability after anterior cruciate ligament (ACL) reconstruction remain unknown. Hypothesis/Purpose: Our objective was to identify patient-reported outcomes and patient-specific risk factors from a large prospective cohort at a minimum 10-year follow-up after ACL reconstruction. We hypothesized that meniscus and articular cartilage injuries, revision ACL reconstruction, subsequent knee surgery, and certain demographic characteristics would be significant risk factors for inferior outcomes at 10 years. Study Design: Therapeutic study; Level of evidence, 2. Methods: Unilateral ACL reconstruction procedures were identified and prospectively enrolled between 2002 and 2004 from 7 sites in the Multicenter Orthopaedic Outcomes Network (MOON). Patients preoperatively completed a series of validated outcome instruments, including the International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), and Marx activity rating scale. At the time of surgery, physicians documented all intra-articular abnormalities, treatment, and surgical techniques utilized. Patients were followed at 2, 6, and 10 years postoperatively and asked to complete the same outcome instruments that they completed at baseline. The incidence and details of any subsequent knee surgeries were also obtained. Multivariable regression analysis was used to identify significant predictors of the outcome. Results: A total of 1592 patients were enrolled (57% male; median age, 24 years). Ten-year follow-up was obtained on 83% (n = 1320) of the cohort. Both IKDC and KOOS scores significantly improved at 2 years and were maintained at 6 and 10 years. Conversely, Marx scores dropped markedly over time, from a median score of 12 points at baseline to 9 points at 2 years, 7 points at 6 years, and 6 points at 10 years. The patient-specific risk factors for inferior 10-year outcomes were lower baseline scores; higher body mass index; being a smoker at baseline; having a medial or lateral meniscus procedure performed before index ACL reconstruction; undergoing revision ACL reconstruction; undergoing lateral meniscectomy; grade 3 to 4 articular cartilage lesions in the medial, lateral, or patellofemoral compartments; and undergoing any subsequent ipsilateral knee surgery after index ACL reconstruction. Conclusion: Patients were able to perform sports-related functions and maintain a relatively high knee-related quality of life 10 years after ACL reconstruction, although activity levels significantly declined over time. Multivariable analysis identified several key modifiable risk factors that significantly influence the outcome. [ABSTRACT FROM AUTHOR]