Purpose <p>Xylazine is a veterinary sedative increasingly detected as an adulterant in illicit opioids that is associated with severe skin and soft-tissue wounds. This study aimed to characterize the musculoskeletal imaging manifestations of xylazine-associated tissue injury in individuals with recreational use and to increase radiologic awareness of this emerging public health problem.</p> Methods <p>This institutional review board–approved retrospective study identified patients with documented recreational xylazine use who underwent musculoskeletal imaging. Demographic data, wound location, clinical characteristics, and photographic documentation were extracted from the electronic medical record and correlated with findings on radiography, CT, MRI, and ultrasound.</p> Results <p>A total of 120 patients were included. Wounds most commonly involved the lower (48%) and upper extremities (48%). Radiographs were obtained in 90% of patients, CT in 62%, MRI in 16%, and ultrasound in 13%. Radiographs frequently demonstrated distortion of soft-tissue planes with prominent periosteal reaction. CT and MRI revealed extensive soft-tissue hypertrophy with ulceration and necrosis of variable depth, often extending to subcutaneous tissues and underlying muscle. Ultrasound was of limited diagnostic value, primarily for assessing wound extent and detecting abscesses. Advanced cases often showed circumferential involvement of an entire limb segment. Acute osteomyelitis was present in 16% and chronic osteomyelitis in 13%, with osseous involvement limited relative to the severity of soft-tissue injury.</p> Conclusion <p>Xylazine-associated wounds demonstrate a distinctive imaging pattern of extensive soft-tissue necrosis and ulceration with marked periosteal reaction but relatively infrequent osteomyelitis. Radiologic evaluation, particularly with radiography and CT, is essential for early recognition, delineation of disease extent, and avoidance of overdiagnosis of osteomyelitis.</p> Graphical Abstract <p></p>