Recently, both red cell distribution width (RDW) and mean corpuscular volume (MCV) have been associated with unfavorable outcomes in several medical conditions. Therefore, we conducted this retrospective study of 1075 patients with stage 3-5 chronic kidney disease to investigate whether interactions between RDW and MCV influence the risk of mortality. These patients were divided into four groups: group A (n = 415), RDW ≤ 14.9% and MCV ≤ 91.6 fL; group B (n = 232), RDW > 14.9% and MCV ≤ 91.6 fL; group C (n = 307), RDW ≤ 14.9% and MCV > 91.6 fL; and group D (n = 121), RDW > 14.9% and MCV > 91.6 fL. The adjusted hazard ratio (HR) of all-cause mortality for group B versus group A was 1.44 (95% confidence interval [CI], 1.14-2.12, p = 0.02), group C versus group A 2.14 (95% CI, 1.31-3.48, p = 0.002), and group D versus group A 5.06 (95% CI, 3.06-8.37, p < 0.001). There was a multiplicative interaction between MCV and RDW in predicting patient mortality. The use of RDW in conjunction with MCV may improve healthcare by identifying those at an increased risk for mortality compared with the use of either RDW or MCV alone.