Insufficient hemoglobin and depression share several symptoms and often occur in the same patients. Here, we sought to clarify their relationship by investigating two indices of oxygenation at the tissue level: mean corpuscular hemoglobin concentration (MCHC) and hemoglobin level. We hypothesized that MCHC would be more informative than hemoglobin levels. This prospective, longitudinal, community-based study included 337 participants (108 men and 229 women; age range, 38-87 years) who received evaluations of MCHC, hemoglobin levels and depressive symptom scores (DSS) during baseline and follow-up examinations, which were performed in 2008-2011 and 2010-2012, respectively. MCHC and hemoglobin levels were measured as part of complete blood counts, while DSS was evaluated using the Beck Depression Inventory. Associations were analyzed using linear regression. We found a statistically significant association between baseline MCHC and follow-up DSS (β = -0.69, p = 0.026), which remained statistically significant after controlling for potential confounders (β = -0.71, p = 0.011). Further, when we analyzed the relationship separately for men and women, we observed that it remained stable for women before (β = -1.00, p = 0.014) and after (β = -1.09, p = 0.003) adjusting for confounders. The stable association indicates that MCHC may be superior to hemoglobin level as a prognostic factor for future depressive symptoms in women. MCHC is easy to measure and low MCHC is usually treatable. Therefore, screening and intervention efforts could be targeted at women with low MCHC, who appear to have elevated risks of developing depressive symptoms.