Paraneoplastic neurological disorders are devastating remote effects of malignancy. Despite compelling evidence of an autoimmune pathogenesis, empiric immunomodulatory treatment of these disorders is often ineffective. However, very few systematic studies have been conducted, and the treatment of patients without active malignancy has not been addressed. We conducted a prospective open-label treatment study of plasma exchange plus conventional cancer chemotherapy (10 patients) or plasma exchange plus continuous oral cyclophosphamide (10 patients). All patients had progressive symptoms and at least moderate disability at enrollment (mean Rankin score, 3.4). Patients who had experienced symptoms for more than 12 months were excluded (mean duration of symptoms at enrollment, 3.6 months). The primary outcome measure was change in quantitative disability measures (Rankin and Barthel scores) after 6 months of treatment; a positive response was defined as stability or improvement in disability. Overall, 50% of patients had a positive response at 6 months (6 patients had improved by at least 1 Rankin grade). Patients with good outcome tended to be those with less disability at time of enrollment. Hematologic toxicity was common among those receiving cyclophosphamide. Aggressive immunosuppression early in the clinical course should be considered in patients who have paraneoplastic neurological disorders, even when there is no evidence of active malignancy.