This study assessed the effects of carbon monoxide (CO) poisoning on the corpus callosum (CC). Sixty-two CO-poisoned patients had MRI scans and a battery of neuropsychological tests within 24 h (day of exposure) of CO poisoning and at 6 months post CO exposure. Serial quantitative magnetic resonance imaging (QMRI) analysis of the CC was carried out, with the day of exposure scans compared to the 6-month scans. There was no difference between normal subjects' CC and the baseline scans in the CO-poisoned patients. We detected a 15-mm2 loss in the cross-sectional surface area of the CC between baseline and the 6-month follow-up scans. The effect on the CC was generalized atrophy rather than CC subregion-specific changes. Neuropsychological test results performed at baseline and at 6 months did not correlate with the level of CC atrophy. Independent of any CC effects, the patients exhibited impaired memory, attention, and executive functioning on baseline testing, with variable improvement in cognitive function at 6 months. Quantitative MRI analysis allows for the detection of subtle CC changes that may not otherwise be observed following CO poisoning. The long-term effects of CO on the brain have been historically underestimated; however, we found subtle but significant CC atrophy and cognitive impairments following CO poisoning.