Delayed posthypoxic demyelination may rarely complicate an episode of severe hypoxia, with or without exposure to carbon monoxide. Following recovery from initial coma, progressive neurologic deterioration ensues with outcomes ranging from death to full recovery. Delayed posthypoxic demyelination is hypothesized to be immunemediated, with support coming from recent animal experiments. We report a 46-year-old man who developed progressive cognitive deficits with abulia approximately 3 weeks after recovering from coma related to alcohol and morphine intoxication. Despite treatment with high-dose steroids and plasmapheresis, he continued to deteriorate and remained in a vegetative state until his death under hospice care more than 2 months after his initial hypoxic insult. Serial brain imaging and postmortem examination showed bilateral necrosis of the globi pallidi and extensive demyelination in the centrum semiovale and corona radiata. Based on an immune-mediated model of disease and given a lack of effective treatments, future use of immunomodulatory therapy may still be worth considering early in the course of this rare and potentially devastating condition.