Thrombotic thrombocytopenic purpura (TTP) is a rare complication of connective tissue diseases. Here, we describe 2 patients with mixed connective tissue disease (MCTD) who had pericardial effusion and TTP. They had moderately low to normal ADAMTS13 activity and no ADAMTS13 neutralizing antibodies. Both patients responded poorly to plasma exchange. One patient died due to multiple organ failure and the other due to infection. Although rare, TTP is an important complication that leads to a poor prognosis in MCTD patients.