Open fracture is a common occurrence in civilian and military populations. Though great strides have been made in limb salvage efforts, persistent muscle strength deficits can contribute to a diminished limb function after the bone has healed. Over the past decade, a growing effort to establish therapies directed at de novo muscle regeneration has produced several therapeutic approaches. As this effort progresses and as therapies reach clinical testing, many questions remain regarding the pathophysiology of the volumetric loss of skeletal muscle. The current study demonstrates, in a rat “open fracture” model, that the volumetric loss of skeletal muscle results in persistent functional deficits that are dependent on muscle length and joint angle. Moreover, the injured muscle has an increased stiffness during passive stretch and a reduced functional excursion. A case study of a patient with an open type III tibia fracture resulting in volumetric muscle loss in the anterior and posterior compartment is also presented. Eighteen months after injury and tibia healing, persistent functional deficits are apparent with many of the same qualities demonstrated in the animal model. Muscle architectural adaptations likely underlie the altered intrinsic functional characteristics of the remaining musculature. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. J Orthop Res 33:40–46, 2015.