Hypersensitivity reactions to 6-mercaptopurine (6-MP) or azathioprine occur during the treatment of inflammatory bowel disease (IBD), raising significant diagnostic and therapeutic challenges. Charts of 591 patient with IBD treated with 6-MP in a single center were retrospectively reviewed. All allergic reactions were recorded along with results of rechallenge, desensitization, and subsequent course of IBD. Sixteen (2.7%) allergic reactions to 6-MP were noted, with fever being the most common (14 cases). Nine of these were rechallenged with 6-MP with recurrence of the same symptoms. Azathioprine was tried in six patients and in five the same symptoms recurred. Four patients underwent successful desensitization to either 6-MP or azathioprine; all four plus another patient who tolerated direct switch to azathioprine entered long-term remission. Among the remaining 11, 5 required surgery, 2 are well on methotrexate, and 4 have chronic symptoms while being treated with other medications. If an allergic reaction to 6-MP occurs during the treatment of IBD, direct switching to azathioprine is probably not justified. Instead, desensitization to either 6-MP or azathioprine should be attempted. Patients who can tolerate these medications after previous allergic reactions have improved outcomes compared with patients who resort to other forms of treatment.