Purpose: Although high-dose chemotherapy supported by autologous peripheral-blood progenitor-cell (PBPC) transplantation improves response rates and survival for patients with multiple myeloma, all patients eventually develop progressive disease after transplantation. It has been hypothesized that depletion of malignant plasma cells from autografts may improve outcome by reducing infused cells contributing to relapse. Patients and Methods: A randomized phase III study using the CEPRATE SC System (Cellpro, Bothell, WA) to enrich CD34+ autograft cells and passively purge malignant plasma cells was completed in 190 myeloma patients randomized to receive an autograft of CD34selected or unselected PBPCs. Results: After CD34 selection, tumor burden was reduced by 1.6 to 6.0 logs (median, 3.1), with 54% of CD34-enriched products having no detectable tumor. Median time to count recovery, number of transfusions, transplantation-related mortality, and days in hospital were equivalent between the two transplantation arms. With a median follow-up of 37 months, 33 patients (36%) in the selected and 34 patients (35%) in the unselected arm had died (P = .784). Median overall survival in the selected arm was reached at 50 months and is not reached at this time in the unselected arm (P = .78). Median disease-free survival was 100 versus 104 weeks (P = .82), with 67% of patients in the selected arm and 66% of patients in the unselected arm relapsing. Conclusion: This phase III trial demonstrates that although CD34 selection significantly reduces myeloma cell contamination in PBPC collections, no improvement in disease-free or overall survival was achieved.