Background: Hyperbaric oxygen (HBO₂) reduced the incidence of cognitive sequelae six weeks post-carbon monoxide (CO) poisoning compared with normobaric oxygen. The apolipoprotein 4 allele predicts unfavorable neurologic outcome after brain injury and stroke. We assessed the effects of the 4 allele on six-week cognitive sequelae following CO poisoning. Methods: We tested apolipoprotein genotypes in 86 of 152 CO-poisoned patients from our randomized trial. Logistic regression was used to control for risk factors while testing for effects with the 4 allele or interactions with 4 and treatment on six-week, six and 12-month cognitive sequelae. Results: We enrolled 86 patients: 44 received HBO₂ and 42 normobaric oxygen therapy. Thirtyone (36%) patients had at least one 4 allele. Six-week cognitive sequelae rates for patients treated with HBO₂ and normobaric oxygen, respectively: 4 allele absent, 11% (3/27) and 43% (12/28); 4 allele present, 35% (6/17) and 29% (4/14). The 4 allele was not associated with six-week cognitive sequelae, 27% (15/55) without and 32% (10/31) with the 4 allele (p=0.323). The interaction between the 4 allele and treatment was significantly associated with six-week cognitive sequelae (p=0.048). The interaction between the 4 allele and treatment was not associated with 6 and 12-month cognitive sequelae. Conclusions: Hyperbaric oxygen therapy reduces cognitive sequelae following CO poisoning in the absence of the 4 allele. Since apolipoprotein genotype is unknown at the time of poisoning, we recommend patients with acute CO poisoning receive HBO₂.