Apolipoprotein E has been implicated in modifying neurological outcome after traumatic brain injury, although the mechanisms by which this occurs remain poorly defined. To investigate the role of endogenous apolipoprotein E following acute brain injury, noninvasive magnetic resonance imaging was performed on anesthetized mice following closed head injury. Effacement of the lateral ventricle was used as a radiographic surrogate for cerebral edema. At 24 hours following injury, apolipoprotein E‐deficient animals had a greater degree of cerebral edema as compared to matched controls. In addition, the brains of apolipoprotein E‐deficient animals had a significantly greater upregulation of tissue necrosis factor α messenger ribonucleic acid as compared to controls as early as 1‐hr post injury. Thus, modulation of the endogenous central nervous system inflammatory response may be one mechanism by which apolipoprotein E affects outcome following acute brain injury.