Treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) frequently includes use of immunosuppressive agents. Controlled treatment trials demonstrating efficacy are available only for prednisone and therapeutic plasma exchange (TPE). When these fail to achieve lasting chemical improvement after reduction or cessation of therapy, subsequent regimens are empiric, often leading to prolonged immunosuppression. It is not possible to predict who will respond to which agent and when. Administered individually, immunosuppressive agents may pose an acceptable risk, but cumulative effects of multiple agents in refractory patients may suppress the immune system and contribute to increased morbidity and mortality. Treatment difficulties with refractory CIDP patients have not been emphasized, and long-term effects of immunosuppression have focused on the risk of malignancy. In reviewing our clinical experience treating over 100 CIDP patients we identified approximately 20 patients who could be considered refractory to multiple immunosuppressive therapies and dependent upon long-term intermittent TPE. Two of these patients exemplify the morbidity associated with CIDP and its associated treatment. Our review of the clinical course of these patients raised issues about the use of multiple immunosuppressive agents, long-term goals, and long-term prognosis in CIDP.