Infliximab is efficacious for refractory Crohn's disease, but delayed hypersensitivity reactions preclude retreatment for patients experiencing this complication. We report the results of four patients offered enrollment in an open label trial of thalidomide as "salvage" therapy for their refractory disease. Two patients with active fistulous disease and two with lumenal disease received open-label thalidomide 200 mg every night and were evaluated monthly at the University of Chicago Clinical Research Center for 12 weeks. Before administration, patients signed an informed consent form discussing the potential risks of thalidomide use. Female patients of child-bearing age underwent serum pregnancy testing every 4 weeks. Response was defined as an absolute decrease in Crohn's Disease Activity Index (CDAI) by 100 points or improvement in two of three clinical parameters for fistulous disease. A patient with a single perirectal fistula had complete closure by 4 weeks, the other had noticeable improvement of five perianal fistulae at 4 weeks and complete closure by 12 weeks. One lumenal patient had a CDAI decrease of 250 points in 4 weeks. The fourth patient withdrew secondary to sedation after only a week of therapy. Two patients (one fistula, one lumenal) continued thalidomide past the 3-month study period and remained in remission at 5 and 7 months. Side effects reported were sedation (four of four patients), hypertension (one of four), and peripheral neuropathy (one of four). Thalidomide appears to be a safe and effective alternative for short-term healing in patients who develop infliximab-induced delayed hypersensitivity reaction and may be an alternative strategy for those at risk.