Acute colonic pseudo-obstruction (ACPO) is a syndrome of massive dilation of the colon without mechanical obstruction that develops in hospitalized patients with serious underlying medical and surgical conditions. Increasing age, cecal diameter, delay in decompression, and status of the bowel significantly influence mortality, which is approximately 40% when ischemia or perforation is present. Evaluation of the markedly distended colon involves excluding mechanical obstruction and other causes of toxic megacolon such as Clostridium difficile infection and assessing for signs of ischemia and perforation. The risk of colonic perforation in ACPO increases when cecal diameter exceeds 12 cm and when the distention has been present for greater than 6 days. Appropriate management includes supportive therapy and selective use of neostigmine and colonoscopy for decompression. Early recognition and management are critical in minimizing complications.