BACKGROUND: Dose-intensive intravenous melphalan with autologous blood stem-cell transplantation induces remission of the plasma cell dyscrasia in a substantial proportion of patients with AL amyloidosis. The impact of this treatment on associated renal disease is not known. OBJECTIVE: To determine the effect of dose-intensive intravenous melphalan and autologous blood stem-cell transplantation on AL amyloidosis-associated renal disease. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENTS: 65 patients with AL amyloidosis and urinary protein excretion greater than 1 g/24 h who received dose-intensive intravenous melphalan and autologous blood stem-cell transplantation between 1 July 1994 and 30 June 1998. MEASUREMENTS: 24-hour urinary protein excretion, serum cholesterol level, serum albumin level, creatinine clearance, urine and serum immunoelectrophoresis, and bone marrow biopsy. Renal response was defined as a greater than 50% reduction in urinary protein excretion in the absence of a 25% or greater reduction in creatinine clearance. Complete hematologic response was defined as absence of detectable monoclonal protein in serum and urine and a bone marrow specimen containing less than 5% plasma cells without clonal dominance of kappa or lambda isotype. RESULTS: Among the 50 patients who survived for at least 12 months, proteinuria, hypoalbuminemia, and hypercholesterolemia improved during follow-up; 36% met criteria for a renal response. Median 24-hour urinary protein excretion decreased from a baseline value of 9.6 g/24 h to 1.6 g/24 h at 12 months among patients with complete hematologic response, and 71% met criteria for a renal response. Twenty-hour urinary protein excretion did not decrease during follow-up among patients with persistent plasma cell disease, and only 11% had a renal response at 12 months (P < 0.001 for hematologic responders vs. nonresponders). CONCLUSION: Dose-intensive intravenous melphalan with autologous blood stem-cell transplantation improves the nephrotic syndrome in patients with AL amyloidosis-associated renal disease. The benefit is largely limited to patients achieving eradication of the underlying plasma cell dyscrasia.