We herein report the cases of two patients with bilateral symmetrical pallidal lesions mimicking hypoxic encephalopathy following severe anemia associated with gastrointestinal hemorrhage despite a lack of carbon monoxide intoxication. Although severe anemia can theoretically result in anemic hypoxia, vulnerable pallidal lesions have rarely been described in anemic patients. Interestingly, both patients shared common conditions associated with atherosclerosis, including heavy smoking, hypertension, type 2 diabetes mellitus and a history of coronary artery bypass grafting for ischemic heart disease. Anemic hypoxia may cause pallidal involvement in atherosclerotic patients with multiple risk factors.