Traumatic brain injury (TBI) can result in significant disability, but outcome is variable. The impact of known predictors accounts for a limited proportion of the variance in outcomes. Apolipoprotein E (ApoE) genotype has been investigated as an additional source of variability in injury severity and outcome, with mixed findings reflecting variable methodology and generally limited sample sizes. This study aimed to examine whether possession of the ApoE ɛ4 allele was associated with greater acute injury severity and poorer long-term outcome in patients referred for rehabilitation following TBI. ApoE genotype was determined for 648 patients with TBI, who were prospectively followed up a mean of 1.9 years post-injury. Hypotheses that ɛ4 carriers would have lower Glasgow Coma Scale (GCS) scores and longer post-traumatic amnesia (PTA) duration were not supported. Prediction of worse Glasgow Outcome Scale-Extended (GOSE) scores for ɛ4 carriers was supported with greater susceptibility seen in females. These results indicate the ApoE ɛ4 allele may be associated with poorer long-term outcome, but not acute injury severity. Possible mechanisms include differential effects of the ɛ4 allele on inflammatory and cellular repair processes, and/or amyloid deposition.