Iron deficiency anemia is commonly encountered in outpatient practice. Gastric acid is one of the important factors for optimum absorption of iron. Proton pump inhibitors are very commonly prescribed medications. One of the debated effects of proton pump inhibitors is on oral iron absorption. Their effect on absorption of oral iron supplementation in iron-deficient patients has not been studied. At the Cooper Hematology Outpatient office, we reviewed charts of iron-deficient anemic patients who were on omeprazole for the last 4 years. Fifty patients having no apparent ongoing blood loss, having other causes of anemia especially that of chronic diseases ruled out, and on omeprazole while starting ferrous sulfate therapy for iron deficiency were selected for chart review. The iron-study results at the start of oral ferrous sulfate therapy and at 3 months follow-up were compared to evaluate the response of ferrous sulfate. The mean hemoglobin change was 0.8 ± 1.2 g/L. The mean change in ferrtin values was 10.2 ± 7.8 μg/L. Only 16% of the patients had a normal response to hemoglobin levels (rise of >2 g/dL), and only 40% had a normal response to ferritin levels (rise of >20 μg/dL). The average age of patients having a suboptimal response to both hemoglobin and ferritin was significantly higher compared with that of the patients with an optimal response. Omeprazole and possibly all proton pump inhibitors decrease the absorption of oral iron supplementation. Iron-deficient patients taking proton pump inhibitors may have to be treated with high dose iron therapy for a longer duration or with intravenous iron therapy.