BACKGROUND: T cells play an important part in Crohn's disease. Immunomodulating therapies that target T cell activation may have clinical effects in Crohn's disease. AIM: To investigate the toxicity and potential efficacy of anti-CD4 monoclonal antibody therapy in patients with Crohn's disease. PATIENTS AND METHODS: A dose escalating pilot study was conducted in three groups of four patients with intractable Crohn's disease, refractory to steroids. They received 70, 210, or 700 mg of cM-T412, a depleting anti-CD4 monoclonal antibody (mAb). RESULTS: The mean reduction in Crohn's disease activity index (CDAI) was respectively 25%, 24%, and 36% at four weeks, and 24% and 52% at 10 weeks in the 210 mg and 700 mg groups. There was only a minor effect on endoscopically evaluated disease activity. Side effects were mild to moderate fever with chills and headache. No signs of opportunistic infection were seen. There was a sustained decrease in CD4 count which lasted at least four weeks in the 70 mg group (76.3 (SD 40.6)% of the baseline value), and 10 weeks in both the 210 mg group (80.8 (SD 60.9)%) and the 700 mg group (24.8 (SD 15.4)%). The primary and secondary humoral immune response was not influenced by anti-CD4 mAb treatment. CONCLUSION: This study shows the moderate potential efficacy of treatment of patients with Crohn's disease using a depleting chimeric monoclonal anti-CD4 antibody.