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To test for an association between apolipoprotein E (APOE) genotypes and duration of intensive care unit delirium.Prospective, observational cohort study.A 541-bed, community-based teaching hospital.Fifty-three mechanically ventilated intensive care unit patients.None.All patients were managed with standardized sedation and ventilator weaning protocols as part of an ongoing clinical trial and were evaluated prospectively for delirium with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). DNA was extracted from whole blood samples obtained on enrollment, and APOE genotype was determined using polymerase chain reaction followed by restriction enzyme digestion by investigators blinded to the clinical information. Delirium occurred in 47 (89%) patients at some point during the intensive care unit stay. Of the 53 patients, 12 (23%) had an APOE4 allele (APOE4+) and 41 (77%) had only APOE2 or APOE3 alleles (APOE4−). APOE4+ patients were younger (53.2 ± 21.9 vs. 65.4 ± 13.4, p = .08) and less often admitted for pneumonia (0% vs. 29.3%, p = .05) compared with APOE4− patients, yet they had a duration of delirium that was twice as long: median (interquartile range), 4 (3, 4.5) vs. 2 (1, 4) days (p = .05). No other clinical outcomes were significantly different between the APOE4+ and APOE4− patients. Using multivariable regression analysis to adjust for age, admission diagnosis of sepsis or acute respiratory distress syndrome or pneumonia, severity of illness, and duration of coma, the presence of APOE4 allele was the strongest predictor of delirium duration (odds ratio, 7.32; 95% confidence interval, 1.82–29.51, p = .005).APOE4 allele represents the first demonstrated genetic predisposition to longer duration of delirium in humans.