There are 16.1 million Americans with major depressive disorder (MDD) and 3.4 million Americans with anemia. Low hemoglobin (Hb) is known to predict depressive symptoms, but seldom is the inverse examined: how does MDD affect Hb? There may be a cyclic relationship in which depression reduces engagement in physical activity and reduced activity lowers Hb. This presents possible implications for young athletes owing to higher depression scores on average than age-matched controls. PURPOSE: To investigate MDD as a predictor of serum Hb levels. METHODS: We analyzed 2,206 patients who were treated at a major hospital. All patients had Glascow Coma Scale scores ≥14, received a complete blood count with differential, and were screened for MDD. Differences in Hb between depressed and non-depressed groups were assessed with independent samples t-tests; multiple linear regression measured the effect of MDD on Hb, controlling for confounding variables. RESULTS: Among depressed patients, Hb was 12.16 ± 1.86 g/dL; among non-depressed patients, Hb was 13.52 ± 1.93 g/dL (p<0.001). This difference was more pronounced among men (14.24 vs. 12.36; p=0.001) than women (12.62 vs. 12.02; p=0.165). Across the total sample, holding constant age, sex, oximetry, blood pressure, use of dialysis, and diagnoses of diabetes, bleeding disorder, cirrhosis, cancer, and respiratory disease, depression associated with a 5.7% reduction in Hb (p=0.035; 95% CI: -1.38 to -0.50 g/dL). The overall model was significant (r2=0.299; p<0.001). Among men, the model retained significance (r2=0.226; p<0.001) and a diagnosis of depression associated with a reduction in Hb of 1.56 g/dL (p=0.002; 95% CI: -2.56 to -0.56 g/dL). CONCLUSIONS: The relationship between Hb and depression may be cyclic. In our population, depression had a greater effect on Hb than diabetes and respiratory diseases, and it had the same effect as bleeding disorders. Depression, via endocrine changes and reductions in physical activity, may lower oxygen- carrying capacity of the blood, and in turn affect endurance performance. Exercise-induced oxidative stress promotes Hb synthesis. For the anemic patient, exercise may enhance mood; for the moody, exercise may enhance oxygen-carrying capacity. For the athlete and the sport psychologist, there may be further implications.