To clarify the role of red blood cell (RBC) lifespan in anemia of multiple myeloma (MM), RBC lifespan was detected in 40 newly diagnosed MM patients by measuring exhaled endogenous carbon monoxide concentration. Mean RBC lifespan was significantly reduced in MM patients (63 ± 23 d) than healthy controls (116 ± 17 d). RBC lifespan in MM patients without anemia (78 ± 21 d) was also significantly lower than for healthy controls. RBC lifespan in MM patients with anemia (52 ± 18 d) was significantly lower than those without. Besides, RBC lifespan in MM patients with renal insufficiency (50 ± 16 d) was lower than those without (66 ± 23 d). RBC lifespan was significantly negatively correlated with % reticulocytes, erythropoietin concentration, % clonal plasma cells, β2-microglobulin (MG) level, and creatinine level. Receiver operator characteristics curve was used to determine a cut-off point (61 d) to predict effect of RBC lifespan on chemotherapy. Overall response rates were significantly higher in MM patients with RBC lifespan ≥61 d than those <61 d. In conclusion, RBC lifespan of MM patients is reduced, and severely shortened RBC lifespan may be involved in the occurrence of anemia in MM patients. The chemotherapeutic effect of MM patients can be predicted by RBC lifespan.