Introduction: Hyperbaric oxygen (HBO2) improves outcome in patients with acute carbon monoxide (CO) poisoning, but optimal dose/timing are unknown. In this double-blind, sham-controlled randomized trial, we compared neuropsychological sequelae at 6 weeks and 6 months in patients receiving 3 HBO2 sessions or 1 HBO2 session and 2 sham chamber sessions after acute CO poisoning. Methods: After completing 1 HBO2 session (3.0 ATA, 60 minutes, 2.0 ATA, 65 minutes), CO-poisoned patients were randomized (1:1): 2 sham chamber sessions (1 ATA air, 120 minutes) or 2 additional HBO2 sessions (2.0 ATA, 90 minutes at pressure, 120 minutes in chamber) completed within 24 hours. Eligible patients were <24 hours from accidental poisoning, English-speaking, and not intubated. We planned 150 participants. Results: The study was stopped early for enrollment futility. From 2006-2016, we screened 395 patients, 136 were deemed eligible to participate, and 75 signed informed consent. Two were later withdrawn for past brain injury/PTSD (1 sham, 1 HBO2), and 1 for performance validity (sham). Of the 72 analyzed, mean age was 42±15 years, 40 (56%) were male, 20 (28%) had loss of consciousness, and mean initial carboxyhemoglobin was 22±9%. The rate of 6-week neuropsychological sequelae was 50% in the 1 HBO2 session group and 55% in the 3 HBO2 sessions group (p=0.80), and at 6 months was 42% vs 46%, respectively (p=0.76). Conclusions: There was no difference in the rate of neuropsychological sequelae in those who received 3 HBO2 sessions and those who received 1 HBO2 sessions and 2 sham sessions. The higher rate of neuropsychological sequelae compared to an earlier study may be due to neuropsychological test-retest effects or previously identified risk factors for cognitive sequelae (age, duration of poisoning, cerebellar dysfunction). This study’s rates of cognitive difficulties, affective complaints, and other symptoms suggest brain injury after CO poisoning is common.