It has been demonstrated that anterior cruciate ligament (ACL) injury-induced cartilage degeneration is the key risk factor for post-traumatic knee osteoarthritis (PTKOA).Pituitary adenylate cyclase-activating polypeptide (PACAP), a common neuropeptide exerting a wide spectrum of functions, has been proved to inhibit inflammation and prevent cartilage degeneration. The current study was performed to investigate circulating and synovial fluid PACAP concentrations in ACL injury patients to determine their relationship with the disease progression of the severity of post-traumatic knee osteoarthritis (PTKOA). 72 ACL injury patients receiving arthroscopical examination and surgery were enrolled in the study. Meanwhile, 60 gender-and-age non-traumatic patellar dislocation patients were enrolled as controls. The VAS score, Lysholm Score and International Knee Documentation Committee (IKDC) score were all recorded to evaluate the clinical severity. Serum and synovial fluid (SF) PACAP levels were investigated by enzyme-linked immunosorbent assay (ELISA).The IL-1β and TNF-α levels were also investigated. The degree of meniscus injury was assessed by MR imaging. The modified Mankin score was recorded to examine the cartilage histopathological alternations. Receiver operating characteristic (ROC) curve was performed to discuss the diagnostic value of PACAP levels for the prediction of the radiographic grading in comparison with IL-1β and TNF-α. Serum PACAP levels between PTKOA patients and patellar dislocation did not reach significant differences. However, SF PACAP levels were significantly lower in PTKOA patients than controls. In addition, SF PACAP levels were negatively associated with MRI imaging grade for meniscus injury and VAS score, and were positively associated with Lysholm and IKDC scores. In addition, SF PACAP levels were negatively related to Mankin score as well as the expressions of IL-1β and TNF-α. ROC analysis curve showed that attenuated PACAP may serve as a favorable marker for the diagnosis of MRI for meniscus injury. SF PACAP concentrations showed an independent and negative association with disease severity in PTKOA following ACL injury. Local treatment with PACAP may act as a possible adjuvant therapy for delaying the process of PTKOA. Copyright © 2019 Elsevier Inc. All rights reserved.