BACKGROUND & AIMS: Higher hemoglobin levels are associated with incident metabolic syndrome (MetS), and higher mean corpuscular volume (MCV) is associated with adverse outcomes. The objective of this study is to evaluate the combined effect of MCV and hemoglobin levels on incident MetS. METHODS: In our cross-sectional study, we analyzed the prevalence of MetS in 20,162 middle-aged Japanese subjects without anemia and with normal MCV levels, as they underwent physical checkups. We subsequently analyzed incident MetS in 11,110 subjects. In order to evaluate the combined effect on incident MetS, the subjects were divided into four study groups according to cutoff values of hemoglobin and MCV for identifying the prevalence of MetS. RESULTS: In the cross-sectional study, hemoglobin (adjusted odds ratio [aOR], 1.02; P < 0.0001 in men and OR, 1.04; P < 0.0001 in women, per 1.0 g/L) and MCV (aOR, 0.93; P < 0.0001 in men and OR, 0.94; P = 0.0005 in women, per 1.0 fL) were independently associated with the prevalence of MetS. In the longitudinal cohort study, hemoglobin (adjusted hazards ratio [aHR, 1.12; P = 0.0006, per 1.0 g/L) and MCV (aHR, 0.96; P < 0.0001, per 1.0 fL) were independently associated with incident MetS in men but not in women. Then, the lower hemoglobin/higher MCV group showed decreased HRs for incidence of MetS compared with other groups of men but not of women. CONCLUSIONS: Among the subjects without anemia and with normal MCV levels, higher hemoglobin or lower MCV levels were associated with higher prevalence of MetS in men and women. In addition, lower hemoglobin with higher MCV showed a decreased risk of MetS in men. We suggested that the assessment of hemoglobin and MCV levels could be used as practical screening tool for MetS.