Extraneurological insults secondary to TBI such as hypotension or hypoxia have been associated with mortality and morbidity. The purpose of this study was to investigate the influence of systemic complications on both neuropsychological outcome and cerebral atrophy. Fifty-seven patients selected from 122 consecutive admissions were studied. Data on the type and severity of injury as well as other systemic insults were collected prior to and during the first 3 days of hospitalization. These data included the presence or absence of a hypoxic episode during the pre-hospital period, the presence and degree of hypoxia, hypercapnia, anemia, hypotension and intracranial hypertension, pupillary reactivity, Glasgow Coma Scale score and coma duration. From the last control CT scan image, performed 6 months post-injury, four different indexes of ventricular dilatation were calculated. Neuropsychological assessment at 6 months included tests of verbal and visual memory, visuoconstructive functions, fine motor speed, and frontal lobe functions. Our results showed that hypoxia and hypotension were related to neuropsychological outcome and long-term ventricular enlargement. Hypoxic episodes prior to hospitalization were related to third ventricle dilatation and to adverse neurological and cognitive outcomes, especially to attention, motor speed, mental flexibility, fluency and verbal memory impairments, suggesting fronto-striatal and hippocampal dysfunction. We conclude that the effect of extraneurological insults on brain structure and function may be as important as the severity of the primary injury.