The aims of this study were to examine in a prospective, randomized trial the efficacy of plasmapheresis in preventing irreversible renal failure in patients with multiple myeloma and to study the renal biopsy tissues from such patients. Twenty-one patients with active myeloma and progressive renal failure were randomized to one of two groups: group 1, forced diuresis and chemotherapy (10 patients), and group 2, forced diuresis, chemotherapy, and plasmapheresis (11 patients). Plasmapheresis and chemotherapy lowered the serum myeloma protein value much more rapidly than chemotherapy alone. Of 5 patients who were oliguric and undergoing dialysis at presentation, only 3 who were treated by plasmapheresis recovered. Of 16 polyuric patients, 5 in group 1 and 7 in group 2 showed improvement in renal function. The main factor that determined irreversibility of renal failure was the severity of myeloma cast formation.