There is now some evidence that major depression is accompanied by biochemical and immune changes pointing to the presence of a chronic inflammatory response. The latter condition is reportedly characterized by changes in iron (Fe) metabolism and the erythron, such as decreased serum Fe and transferrin (Tf) and increased serum ferritin, lower number of red blood cells (RBC), lower hematocrit (Htc) and hemoglobin (Hb). The aim of the present study was to examine Fe metabolism and the erythron in 38 major depressed subjects versus 15 normal volunteers, as well as the effects of antidepressant treatments on these variables. Major depressed subjects had significantly lower serum Fe and Tf, a lower number of RBC, lower Htc and Hb, and a significantly increased number of reticulocytes than normal controls. Serum ferritin was significantly higher in major depressed patients with melancholia than in those with simple major depression and normal controls. Mean corpuscular volume (MCV), MC Hb (MCH), MC Hb concentration (MCHC) and RBC distribution width (RDW) were not significantly different between major depressed subjects and normal controls. Treatment with antidepressants during 5 weeks had no significant effect on the alterations in number of RBC and reticulocytes, Htc, Hb, Fe and Tf. There were significant relationships between the above Fe and erythron variables and established immune-inflammatory markers of major depression, e.g., lowered serum albumin and zinc and the increased electrophoretically-separated alpha 1-globulin fraction. The results suggest that the disorders in Fe metabolism and the erythron during major depression may be induced by the immune-inflammatory response in that illness.