Toxic megacolon is an infrequent but life-threatening complication that occurs most commonly in patients with severe ulcerative colitis. Intravenous steroids are often recommended for patients with toxic megacolon secondary to ulcerative colitis. However, steroid dependency may mask the presence of intra-abdominal sepsis and is associated with refractoriness, during which cytomegalovirus reactivation may occur. In this report, we present two rare cases of megacolon accompanying pancolonic severe ulcerative colitis that were successfully treated with oral tacrolimus, including one steroid-naïve patient. In cases of ulcerative colitis with megacolon, treatment with oral tacrolimus is recommended, thereby avoiding steroid dependency and improving the long-term prognosis.