The aim of this study was to assess the potential of leflunomide, an immunosuppressant in rheumatoid arthritis, as a second-line immunosuppression treatment of patients with Crohn's disease refractory or intolerant to azathioprine. The study cohort consisted of 24 patients. The primary end point was steroid-free remission, and secondary end points were changes in the Crohn's disease activity index (CDAI) and steroid intake, responsiveness of arthralgias and adverse events. Results were expressed in medians (quartiles). The remission rate increased from 21 to 42% by week 16 (P < 0.05). In the intention-to-treat analysis, the CDAI decreased from 219 to 87 (P = 0.018) and the steroid intake from 25 to 3 mg/day (P = 0.033). In the per-protocol analysis, the CDAI decreased from 182 to 87 (P = 0.0183) and the steroid intake from 45 to 4 mg/day (P = 0.0778). Patients with arthralgias improved significantly. However, adverse side effects were frequent. Leflunomide may improve disease activity, especially in terms of arthralgias, and reduce steroid intake. Adverse events were more frequent in our patients than has been reported in controlled studies for rheumatoid arthritis but corresponded to those found in post-marketing studies.