To determine whether the periosteal response to skeletal trauma is impaired when muscle is also injured, thereby providing a possible explanation for why fractures with extensive soft-tissue damage may take longer to heal. A bone defect was made in the tibia of male Fisher rats, and the proliferative response, osteoblast concentration, and callus formation that occurred within 7 days were measured in the presence and absence of simultaneously administered model soft-tissue injury (removal of 10% of the anterior tibialis muscle from a region within 2 to 3 mm of the bone defect). Measurements were made by using autoradiography, quantitative histology, and morphometry. Addition of the muscle injury increased proliferation in the cambium and in the fibrous periosteum on day 1, but had no effect thereafter; proliferation of fibroblasts in the loose connective tissue above the periosteum was not affected. Addition of the muscle injury resulted in increased osteoblast levels 2 to 5 days after injury but had no effect on the amount of callus produced. The inflammatory milieu created by the muscle injury unexpectedly resulted in an increased periosteal response to skeletal trauma, suggesting that inflammatory mediators generated in response to wounding of soft tissues are unlikely to account for delayed fracture healing. These findings may indicate that surgical trauma associated with internal fixation by using plates and screws may not be as deleterious to the fracture-healing response as previously thought.