INTRODUCTION:Anterior cruciate ligament (ACL) injury can result in joint instability, decreased functional performance, reduced physical activity and quality of life and an increased risk for post-traumatic osteoarthritis. Despite the development of new treatment techniques and extensive research, the complex and multifaceted nature of ACL injury and its consequences are yet to be fully understood. The overall aim of the NACOX study is to evaluate the natural corollaries and recovery after an ACL injury. METHODS AND ANALYSIS:The NACOX study is a multicentre prospective prognostic cohort study of patients with acute ACL injury. At seven sites in Sweden, we will include patients aged 15-40 years, within 6 weeks after primary ACL injury. Patients will complete questionnaires at multiple occasions over the 3 years following injury or the 3 years following ACL reconstruction (for participants who have surgical treatment). In addition, a subgroup of 130 patients will be followed with clinical examinations, several imaging modalities and biological samples. Data analyses will be specific to each aim. ETHICS AND DISSEMINATION:This study has been approved by the regional Ethical committee in Linköping, Sweden (Dnr 2016/44-31 and 2017/221-32). We plan to present the results at national and international conferences and in peer-reviewed scientific journals. Participants will receive a short summary of the results following completion of the study. TRIAL REGISTRATION NUMBER:NCT02931084.