Background Delirium occurs in up to 80% of intensive care patients and is associated with poor outcomes. The biological cause of delirium remains elusive. Objectives To determine if delirium and recovery are associated with serum levels of interleukins and apolipoprotein E over time and with apolipoprotein E genotype. Methods The sample consisted of 77 patients with no previous cognitive deficits who required mechanical ventilation for 24 to 96 hours. Daily serum samples were obtained for enzyme-linked immunosorbent assay measurements of interleukins 6, 8, and 10 and apolipoprotein E. DNA extracted from blood was analyzed for apolipoprotein E genotyping. The Confusion Assessment Method for the Intensive Care Unit was administered daily on days 2 through 9. Results Among the 77 patients, 23% had no delirium, 46% experienced delirium, and 31% experienced coma. Additionally, 77% had delirium or coma (acute brain dysfunction), and compared with other patients, had fewer ventilator-free days ( P = .03), longer stay ( P = .04), higher care needs at discharge ( P = .001), higher mortality ( P = .02), and higher levels of interleukin 6 ( P = .03), and the APOE*3/*3 apolipoprotein E genotype ( P = .05). Serum levels of apolipoprotein E correlated with levels of interleukins 8 and 10. Patients with the E4 allele of apolipoprotein E had shorter duration of delirium ( P = .02) and lower mortality ( P = .03) than did patients without this allele. Conclusions Apolipoprotein E plays a complex role in illness response and recovery in critically ill patients. The relationship between apolipoprotein E genotype and brain dysfunction and survival is unclear.