Although anemia is a common finding among human immunodeficiency (HIV)-infected infants in sub-Saharan Africa, the factors contributing to the pathogenesis of anemia have not been well characterized. We sought to characterize the relative contribution of iron deficiency and chronic disease to the anemia among infants. Hemoglobin, ferritin, erythropoietin, tumor necrosis factor-alpha (TNF-alpha), neopterin, CD4(+) lymphocyte count and plasma HIV load were measured in 165 HIV-infected and 39 uninfected 9-mo-old infants seen in an outpatient pediatric clinic in Kampala, Uganda. Among HIV-infected and uninfected infants, the prevalence of anemia (hemoglobin < 110 g/L) was 90.9 and 76.9%, respectively (P = 0.015), and the prevalence of iron deficiency anemia (hemoglobin < 110 g/L and ferritin < 12 microg/L) was 44.3 and 45.4%, respectively (P = 0.92). The relatively higher prevalence of anemia among HIV-infected infants was attributed to the anemia of chronic disease. Among infants with and without iron deficiency, the fitted regression line was log(10) plasma erythropoietin = 2.86 - 0.016.hemoglobin, and log(10) plasma erythropoietin = 4.11 - 0.028.hemoglobin, respectively, with a difference in the slope of the regression lines between log(10) erythropoietin and hemoglobin among infants with and without iron deficiency (P = 0.049). Infants in Uganda have an extremely high prevalence of anemia, and nearly half of the anemia is due to iron deficiency. The erythropoietin response to anemia appears to be upregulated among infants with iron deficiency.