Treatment of Graves' disease (GD) with the B-lymphocyte depleting agent rituximab in addition to standard methimazole-therapy prolongs remission. Paradoxically, it does not mediate a reduction in thyrotropin receptor antibody (TRAb) levels over that of methimazole monotherapy. Using a bioassay involving Chinese hamster ovary cells transfected with the human thyrotropin receptor, we found that the stimulatory capacity of TRAbs was reduced markedly, by 66+/-22%, upon treatment with rituximab and methimazole for 21 days (p<0.0001), compared to an increase by 33% on average (NS) in patients receiving methimazole alone (p=0.04 between groups). The overall levels of TRAbs decreased by around 15% in both groups. Within one year of follow-up, rituximab therapy mediated specific decreases in thyroid-peroxidase antibody- and IgM levels, whereas IgG levels were unaffected. The data indicate that rituximab therapy has differential effects on pathogenic and non-pathogenic autoantibodies, even when directed against the same antigen. The possible mechanisms underlying this hitherto unappreciated phenomenon are discussed.