Investigations of the basic pathological, cellular, and molecular mechanisms of traumatic brain injury (TBI) over the past two decades have been carried out primarily in rodents. Unfortunately, these studies have not translated into improved outcome in patients with TBI. To better model human TBI, a swine model of controlled cortical impact (CCI) was developed. A CCI device was used to generate a focal lesion in 23 anesthetized male Yorkshire swine. In 10 swine, CCI parameters of velocity and dwell time were varied to achieve a consistent injury (3.5 m/sec, 400 msec, respectively). In 13 swine, depth of depression was varied from 9 to 12 mm. Physiological data, including heart rate (HR), mean arterial blood pressure (MAP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP), were collected for 10 h after injury. Following injury, ICP and HR increased above baseline values in all swine, with a more pronounced elevation in animals impacted to a depth of depression of 12 mm. An 11-mm depth of depression was found to most closely mimic pathological features of human TBI with edema, infiltration of inflammatory cells, pericapillary hemorrhage, and petechial hemorrhages in the white matter. Injury to a depth of depression of 12 mm resulted in cortical laceration obscuring these features. Immunohistological staining with Neu-N, MAP-2, and Fluoro Jade B revealed evidence of degenerating neurons, axonal disruption, and impending cell death. These results indicate that the swine model of CCI results in a defined and reproducible injury with pathological features similar to human TBI. Physiological parameters after injury are readily monitored in a setting mimicking conditions of an intensive care unit, establishing a more clinically relevant experimental model for future investigations.