Background <p>Several studies have examined the relationship between mean corpuscular volume (MCV) and prognosis of patients with colorectal cancer (CRC); however, these findings have been inconsistent. This study aimed to investigate the association between the preoperative MCV and recurrence-free survival (RFS) in patients with CRC.</p> Methods <p>We analyzed 1876 patients with stage II/III CRC who underwent R0 resection. The relationships between clinicopathological factors and RFS were investigated using univariate and multivariate analyses. The prognostic significance of the MCV was examined in various clinicopathological contexts. Anemia was defined as Hb &lt; 13&#xa0;g/dL in men and Hb &lt; 12&#xa0;g/dL in women.</p> Results <p>The mean patient age was 69 ± 11&#xa0;years. The 5-year RFS rate was 73.3%. Multivariate analysis showed that tumor location, histological grade, stage, serum carcinoembryonic antigen level, carbohydrate antigen 19-9, neutrophil/lymphocyte ratio, and MCV were significant independent risk factors for RFS. Hazard ratios for recurrence were 0.60 for MCV &lt; 80 fL and 1.76 for MCV ≥ 100 fL, compared to MCV 80–100 fL (<i>p</i> &lt; 0.033). The 5-year RFS rates were 83.4% and 58.9%, respectively. This trend was more pronounced in patients with anemia and was contradictory in those without anemia.</p> Conclusion <p>MCV &lt; 80 fL and ≥ 100 fL can be an indicator of favorable and worse RFS, respectively, in patients with stage II/III CRC and anemia.</p>