OBJECTIVE To better characterize the association between type I interferons and ischemic colitis (IC) in patients with the hepatitis C virus (HCV) and multiple sclerosis (MS), by analyzing reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) and the published literature. DATA SOURCES A total of 2,562,390 reports of adverse events between January 2003 and June 2011 were downloaded from the FDA AERS. A literature review was performed on PubMed (January 1966–August 2012) using the MeSH terms interferon or interferon alfa or interferon beta and ischemic colitis separated by the Boolean operator “and” between the first 3 terms and the last term. Additional literature was identified by conducting a hand search of the reference list of the published literature identified in the initial search. STUDY SELECTION AND DATA EXTRACTION Cases were restricted to those with an indication of HCV or MS, a primary suspect drug of a type I interferon, and a reaction of IC. Full-length reports were requested and organized by type of interferon, age, sex, concomitant drugs, and comorbidities. The Naranjo prob a bility scale was used to define cases as definite, probable, possible, or doubtful drug-induced adverse events. DATA SYNTHESIS Type I interferons, including interferon alfa (IFN-α) and interferon beta (IFN-β), are approved for the treatment of HCV and MS. IFN-α has been shown to induce IC, but a relationship between type I interferons and IC has not been clarified in the medical literature. Fifty-six primary suspect reports of type I interferons associated with IC in patients with HCV or MS were identified from the FDA AERS. Seventeen cases were reported with IFN-α and 39 cases were reported with IFN-β. The majority of the cases were in females (80%) and those between the ages of 50 and 65 years (52%). The Naranjo probability scale identified 13 probable and 4 possible cases of IFN-α–induced IC, and 19 probable and 20 possible cases of IFN-β–induced IC. In the literature, 11 cases of IFN-α–induced IC were reported, while there were no reports with IFN-β. CONCLUSIONS Our study suggests a possible association between treatment with type I interferons and the development of IC. Further research to determine the mechanism of this association is warranted.