The physiological function of the normal cellular form of prion protein (PrPC) is not yet fully understood. In the current study we used prion protein gene knock-out mice (Prnp(-/-)) to assess the role of PrPC in traumatic brain injury. Prnp(+/-) and Prnp(-/-) mice were subjected to weight-drop contusional brain injury over the left parietal cortex. Prnp(-/-) mice manifested a significantly larger lesion volume and worse neuromotor scores than did their Prnp(+/-) litter-mates. IgG immunostaining revealed that in Prnp(-/-) mice the breakdown in the blood-brain barrier (BBB) was more extensive at 1 month after brain injury. Our results are in agreement with previous in vitro findings of the neuroprotective role of PrPC and further support the hypothesis that functional loss of PrPc plays a pathogenic role in prion diseases. We also suggest that PrPc modulates BBB function.