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Thrombotic thrombocytopenic purpura (TTP) causes significant morbidity and mortality, and may be associated with connective tissue diseases (CTD). Some cases are refractory to plasma exchange and require immunosuppressive therapy. We describe 2 patients with CTD who had refractory TTP treated successfully with rituximab. Both patients also developed heparin-induced thrombocytopenia (HIT). The propensity of a patient with a CTD to develop autoantibodies to ADAMTS-13 and platelets likely explains the association of such a disease with TTP and HIT. Rituximab should be considered in this complex clinical setting, because it may decrease the production of multiple pathogenic autoantibodies.