OBJECTIVE To assess the risk of infection in patients with systemic lupus erythematosus (SLE) treated with plasmapheresis in addition to intravenous (I.V.) pulse cyclophosphamide (CYC). METHODS We searched the records of all our SLE patients for those who had undergone plasmapheresis plus I.V. CYC treatment (n = 9). Consecutive patients with similarly high SLE activity who underwent I.V. CYC therapy but not plasmapheresis were included as controls (n = 12). We evaluated both groups for severe infections, outcome, and confounding clinical variables. RESULTS Seven of 9 plasmapheresis-treated patients had serious bacterial or viral infections, including 3 cases of cytomegalovirus infections. Among the 12 patients treated with I.V. CYC alone, only 2 had severe infections (P < 0.01). Three patients in the plasmapheresis group and none in the control group died of infections. Treatment efficacy, however, was similar for both groups. CONCLUSIONS Among SLE patients treated with plasmapheresis and I.V. CYC, life-threatening bacterial and viral infections and mortality occur more frequently than among patients with similarly active SLE treated with I.V. CYC alone.