CONTEXT: In patients with coexisting iron-deficiency anemia and subclinical hypothyroidism, anemia does not adequately respond to oral iron therapy. OBJECTIVE: We studied whether iron-deficiency anemia might indicate treatment of subclinical hypothyroidism. DESIGN: Patients were assigned to a control or experimental group: 240 mg/d oral iron alone (iron group) or 240 mg/d oral iron plus 75 microg/d levothyroxine (iron/levothyroxine group). Levels of hemoglobin, hematocrit, red blood cell count, serum iron levels, ferritin, total iron-binding capacity, TSH, and free T(4) were measured before and after treatment. SETTING: The study was conducted at a university hospital outpatient clinic. Patients: Fifty-one patients with coexisting iron-deficiency anemia and subclinical hypothyroidism participated in the study. Intervention: Patients were treated as described above in either the iron group or the iron/levothyroxine group. MAIN OUTCOME MEASURE: A clinically satisfactory increase in hemoglobin was regarded as successful. Results: Mean hemoglobin levels increased by 0.4 g/dl in the iron group [95% confidence interval (CI) 0.2-0.7, P = 0.001], whereas it increased by a mean of 1.9 g/dl in the iron/levothyroxine group (95% CI 1.5-2.3, P < 0.0001). The increase in serum iron was greater in the iron/levothyroxine group by a mean of 47.6 microg/dl (95% CI 34.5-60.6, P < 0.0001). Increases in hemoglobin, red blood cells, hematocrit, and serum ferritin levels after treatment were statistically significantly greater in the iron/levothyroxine group (P < 0.0001). Starting hemoglobin and increase in hemoglobin were negatively correlated in the iron/levothyroxine group (r = -0.531, P = 0.006). CONCLUSIONS: Subclinical hypothyroidism should be treated in iron-deficiency anemia patients when both conditions coexist. This would provide a desired therapeutic response to oral iron replacement and prevent ineffective iron therapy.