Secondary osteoarthritis after ligament or meniscus injury generally causes great burdens to patients. Alpha-melanocyte-stimulating hormone (α-MSH ), a 13 amino acid neuropeptide produced by intracellular cleavage of the proopiomelanocortin (POMC) hormone, has been proven to suppress inflammation and protect cartilage from damage. The present study was carried out to explore the relationship between synovial fluid α-MSH levels and articular cartilage degeneration in patients with anterior cruciate ligament (ACL) deficiency.51 patients with ACL deficiency admitted to our hospital were enrolled. The Noyes score method was used to assess articular cartilage damage arthroscopically. Synovial fluid α-MSH levels were examined using a double antibody radioimmunoassay method. Inflammation markers such as IL-6, MMP-3, and degradation biomarker of collagen type II (CTX-II) were also explored by enzyme-linked immunosorbent assay (ELISA).The articular cartilage in ACL deficiency patients deteriorated significantly with time after injury (r = 0.673, p < 0.001). Synovial fluid α-MSH levels are inversely associated with Noyes scores (r = -0.682, p < 0.001), levels of inflammation markers IL-6 (r = -0.302, p = 0.035), MMP-3 (r = -0.652, p < 0.001) and degradation biomarker CTX-II (r = -0.584, p < 0.001).Synovial fluid α-MSH levels showed an independent and negative correlation with articular cartilage degeneration in patients with knee ACL deficiency. Supplementing with a-MSH may serve as a possible adjuvant therapy for delaying cartilage degeneration after ACL injury.