Study Design Clinical measurement, cross-sectional. Background Individuals who have undergone anterior cruciate ligament (ACL) reconstruction commonly experience long-term impairments in quality of life (QoL), which may be related to persistent knee symptoms or radiographic osteoarthritis (ROA). Understanding the impact of knee symptoms and ROA on QoL after ACL reconstruction may assist in the development of appropriate management strategies. Objectives To (1) compare QoL between groups of individuals after ACL reconstruction (including those who are symptomatic with ROA, symptomatic without ROA, and asymptomatic [unknown ROA status]), and (2) identify specific aspects of QoL impairment in symptomatic individuals with and without ROA post ACL reconstruction. Methods One hundred thirteen participants completed QoL measures (Knee injury and Osteoarthritis Outcome Score QoL subscale [KOOS-QoL], Anterior Cruciate Ligament Quality of Life [ACL-QoL], Assessment of Quality of Life-8 Dimensions [AQoL-8D]) 5 to 20 years after ACL reconstruction. Eighty-one symptomatic individuals underwent radiographs, and 32 asymptomatic individuals formed a comparison group. Radiographic osteoarthritis was defined as a Kellgren-Lawrence grade of 2 or greater for the tibiofemoral and/or patellofemoral joints. Mann-Whitney U tests compared outcomes between groups. Individual ACL-QoL items were used to explore specific aspects of QoL. Results In symptomatic individuals after ACL reconstruction, ROA was related to worse knee-related outcomes on the KOOS-QoL (median, 50; interquartile range [IQR], 38-69 versus median, 69; IQR, 56-81; P<.001) and the ACL-QoL (median, 51; IQR, 38-71 versus median, 66; IQR, 50-82; P = .04). The AQoL-8D scores showed that health-related QoL was impaired in both symptomatic groups compared to the asymptomatic group. The ACL-QoL item scores revealed greater limitations and concern surrounding sport and exercise and social/emotional difficulties in the symptomatic group with ROA. Conclusion Osteoarthritis is associated with worse knee-related QoL in symptomatic individuals after ACL reconstruction. Diagnosing ROA in symptomatic individuals after ACL reconstruction may be valuable, because these individuals may require unique management. Targeted strategies to facilitate participation in satisfying activities have potential to improve QoL in symptomatic people with ROA after ACL reconstruction. J Orthop Sports Phys Ther 2018;48(5):398-408. doi:10.2519/jospt.2018.7830.