Approximately 50 % of patients with inflammatory bowel disease (IBD) suffer from anaemia, with Fe deficiency being the most common cause. CD52 monoclonal antibody (mAb) targets the cell surface CD52 and is effective in depleting lymphocytes through cytolytic effects in vivo. The aim of the present study was to investigate the therapeutic effect of anti-mouse CD52 mAb on Fe-deficient anaemia in IBD. IL-10 knockout mice (IL-10− / −) of 12 weeks with established colitis were treated with anti-mouse CD52 mAb once per week for 2 weeks. Severity of colitis, blood T lymphocytes, blood Hb, haematocrit, plasma erythropoietin (EPO), serum Fe concentration, transferrin saturation, splenic Fe stores, expression of liver hepcidin mRNA, Western blotting of the phosphorylated form of Smad1/5/8 and total Smad1 were measured at the end of the experiment. IL-10− / − mice treated with CD52 mAb showed a reduction in the percentage of CD4+ and CD4+CD45+ T cells in blood and weight loss typically associated with colonic inflammation, serum levels of EPO, the expression of liver hepcidin mRNA and total Smad1 protein, while they showed an increase in Hb concentrations, haematocrit, levels of serum Fe, transferrin saturation and splenic Fe stores. The present results indicated that anti-CD52 therapy may ameliorate Fe-deficient anaemia by reducing colonic inflammation. These findings may open novel horizons in the treatment of patients with IBD by resetting of immunological homeostasis in the gut by depleting the activated T cells in the gut mucosa.