Significant traumatic brain injury (TBI) is nearly always associated with cognitive deficits, but in a highly variable manner. Apolipoprotein E (ApoE) plays a pivotal role in CNS response to injury. To examine the association of ApoE genotype with long-term outcome in TBI patients, we determined the ApoE genotype from 61 TBI patients who had been injured over three decades earlier. All patients had been studied neuropsychologically after their injuries. The long-term outcome was evaluated with repeated neuropsychological testing and by applying various measures of everyday functioning and quality of life. After three decades, TBI patients with the ApoE epsilon4 allele showed significantly poorer general cognitive level than those without this allele. This decline was wholly accounted for by a subgroup of these patients who had developed incident or clinical dementia, while the majority of the ApoE epsilon4 positive patients showed no decline at all. The other outcome measures describing vocational, physical, or subjective symptom outcome did not show significant relationships to the ApoE genotype. A portion of the TBI patients with the ApoE epsilon4 allele seem to be at risk of long-term cognitive decline.