Myxedema megacolon is a rare manifestation of hypothyroidism. It may respond to appropriate treatment but is sometimes irreversible, resulting in fatal complications. Two possible mechanisms to explain the colonic atony include (1) myxomatous infiltration of the submucosa with separation of the muscular fibers from the ganglia of Auerbach's plexus, and (2) severe autonomic neuropathy affecting the extrinsic nerves to the colon and the myenteric plexus. Histology from our case supports the first proposed mechanism. Urecholine challenge and manometric measure response may help predict reversibility of colonic atony. Treatment should be individualized and should include factors such as age, duration of symptoms, and other medical illness. Low-dose oral or intravenous triiodothyronine is effective. Hypothyroidism following external radiation of the neck for lymphoma is not uncommon, and the risk increases following one or more lymphangiograms. Such patients should be followed up with regular TSH estimations for at least three years.