The purpose of the study was to examine the yield of CD34+ cells, response rates, and toxicity of high-dose cyclophosphamide with or without etoposide in patients with multiple myeloma. In total, 77 myeloma patients received either cyclophosphamide 4.5 g/m2 (n=28) alone or with etoposide 2 g/m2 (n=49) in a nonrandomized manner, followed by G-CSF 10 μg/kg/day for the purpose of stem cell mobilization. The effects of various factors on CD34+ cell yield, response rate and engraftment were explored. A median of 22.39 × 106 CD34+ cells/kg were collected on the first day of leukapheresis (range 0.59-114.71 × 106/kg) in 71 (92%) of patients. Greater marrow plasma cell infiltration (P=0.02) or prior radiation therapy (P=0.02) adversely affected CD34+ cell yield. In total, 45% of patients receiving cyclophosphamide and 56% of those receiving cyclophosphamide/etoposide had at least a minimum response by EBMT criteria. In all, 25% of patients who received cyclophosphamide alone vs 75.5% of patients who received combined chemotherapy required hospitalization mainly for treatment of neutropenic fever. Cyclophosphamide alone is associated with impressive CD34+ cell yields and clear antimyeloma activity. The addition of etoposide resulted in increased toxicity without significant improvement in CD34+ cell yield or response rates.