Wegener's granulomatosis (WG) is a chronic, relapsing, systemic autoimmune disease. Rituximab, a monoclonal antibody against human CD20, has shown promise as a novel treatment for WG. The monitoring of therapeutic B-cell 'depletion' by peripheral blood flow cytometry has been proposed to help monitor rituximab therapy. We report the case of a patient with known WG and granulomatous disease, successfully treated with rituximab, who relapsed whilst peripheral blood monitoring apparently indicated persistent B-cell depletion. Further investigations demonstrated CD20(+) B cells in tissue at sites of active disease. The implications for disease pathogenesis and clinical monitoring of disease are discussed.