Irritable bowel syndrome (IBS) is one of the most common entities observed by both primary care physicians and gastroenterologists. Alosetron is a potent and selective serotonin antagonist that recently became the first Food and Drug Administration-approved agent for diarrhea-predominant IBS. However, since approval, significant side effects have been noted with the use of alosetron including severe constipation, fecal impaction, and ischemic colitis. We describe a case of ischemic colitis in a male patient with IBS who was briefly treated with alosetron. Clinical, endoscopic, and pathologic features of the focal colitis strongly suggested ischemia. Symptoms correlated temporally with alosetron use, and symptoms abated with discontinuation of the drug. Endoscopic and pathologic resolution of the colitis were documented.