Equine Interleukin-1 Receptor Antagonist (IL-1Ra) is an anti-inflammatory cytokine produced by monocytes, macrophages, neutrophils, and synoviocytes in horses (Equus caballus) that functions as a key regulator of IL-1–mediated inflammation. IL-1Ra competitively binds to the IL-1 receptor type 1 (IL-1R1) without activating downstream signaling, thereby blocking the pro-inflammatory effects of IL-1α and IL-1β and limiting activation of NF-κB and MAPK pathways that drive fever, leukocyte recruitment, cartilage degradation, and systemic inflammatory responses. In equine health, IL-1Ra plays a particularly important role in musculoskeletal diseases such as osteoarthritis and synovitis, where it counteracts IL-1β–induced cartilage matrix breakdown and joint inflammation. Autologous conditioned serum (ACS) and other regenerative therapies used in performance horses often aim to increase intra-articular IL-1Ra concentrations to modulate joint inflammation. IL-1Ra is also relevant in conditions such as laminitis, colitis, endotoxemia, and systemic inflammatory response syndrome (SIRS), where balanced IL-1 signaling influences disease severity and recovery. As both a biomarker and therapeutic target, equine IL-1Ra is central to veterinary sports medicine and inflammatory disease management. In translational research, horses serve as valuable large-animal models for human osteoarthritis and inflammatory joint disease, and characterization of equine IL-1Ra supports studies of cytokine regulation, inflammasome biology, and development of targeted anti-inflammatory therapies relevant to both equine and human health.