A patient with iron deficiency anemia does not improve after 3 months of therapy. What is the most likely explanation?

When iron deficiency anemia fails to respond to three months of oral iron therapy, the most clinically important explanation to investigate is ongoing chronic blood loss. Iron supplementation replaces iron stores, but if blood — and therefore iron — is continuously being lost, the replacement cannot outpace the depletion. Common sources of chronic blood loss include gastrointestinal bleeding from colorectal cancer, peptic ulcers, or inflammatory bowel disease, as well as heavy menstrual bleeding in women. Identifying and treating the source of blood loss is essential before the anemia can resolve. Bone marrow failure would produce pancytopenia rather than isolated iron deficiency anemia, and the clinical picture would typically include additional abnormalities in white blood cells and platelets, making this a less likely explanation. Excess iron would not cause iron deficiency anemia to persist — iron overload is the opposite problem and is associated with hemochromatosis rather than inadequate response to supplementation. Pernicious anemia is caused by vitamin B12 deficiency due to lack of intrinsic factor and presents with megaloblastic anemia and neurological symptoms; it would not respond to iron therapy at all, but would represent a different diagnosis rather than treatment failure of an existing iron deficiency diagnosis. Chronic blood loss is the priority consideration to investigate.