Renal impairment (RI) is a frequent complication with higher incidence of infections and an important prognostic factor for survival. Melphalan clearance is renal function dependent whereas cyclophosphamide is renal function independent. We investigated which combination regimen should be selected between melphalan-combining regimen (MPT) or cyclophosphamide-combining regimen (TCD) in elderly multiple myeloma (MM) patients with RI. Between 2005 and 2009, 157 newly diagnosed MM patients with RI were included comparing MPT with TCD therapy as initial treatment. Seventy-four patients were given MPT regimen, and 83 patients were given TCD regimen. Baseline characteristics were similar between the MPT and TCD groups. Analysis of different cutoff levels between 25% and 75% quartiles using log-rank test determined that glomerular filtration rate (GFR), 40 ml/min/1.73 m(2) as the cutoff point, yielded the highest difference in event-free survival (EFS) and overall survival (OS). The MPT subgroup with low GFR (GFR <40 ml/min/1.73 m(2)) had poorer response rates than others. The incidence of neutropenia and infection with febrile neutropenia were higher in the MPT subgroup with low GFR than the others (p = 0.016, p < 0.001). Furthermore, mortality due to the infection was higher in the MPT subgroup with low GFR than the others (p < 0.001). EFS was lower in the MPT subgroup with low GFR than the others (p < 0.001). OS was lower in the MPT subgroup with low GFR than the others (p < 0.001). In newly diagnosed elderly MM patients with RI, TCD regimen would be an effective and tolerable treatment option due to the combination of cyclophosphamide independent to renal function and dexamethasone effective for RI.