Induction of lymphocytic proliferation has been postulated to be a mechanism whereby plasmapheresis may enhance the action of cytotoxic immunosuppressive drugs. This study found increased spontaneous proliferation of peripheral blood mononuclear cells following intensive plasmapheresis treatment of patients with multiple sclerosis (MS) or Guillain-Barré syndrome (GBS). The increased proliferative response was reduced below baseline in four of six MS patients who received subsequent immunoglobulin intravenous (IGIV) and pulsed cyclophosphamide therapy, but not in three MS patients receiving IGIV alone. In five GBS patients with low baseline proliferation, proliferation also increased after plasmapheresis. High baseline proliferation found in three GBS patients may have reflected antecedent infection, since it fell during plasmapheresis in the two patients in whom it was measured. Plasmapheresis could possibly augment the effectiveness of cytotoxic drugs in controlling autoimmunity by inducing lymphocytes to proliferate, thereby making them more susceptible to drug action.