BACKGROUND: The prevalence of iron deficiency in pediatric sickle cell disease (SCD) is difficult to describe because standard markers of iron metabolism are altered in this inflammatory state. Soluble transferrin receptor (sTfR) is an alternative marker of iron utilization. Our primary objective was to evaluate the utility of sTfR as a biomarker of hemolysis and erythropoietic drive versus iron metabolism in SCD. PROCEDURE: In a prospective cohort study, we screened 51 children with SCD at steady state with markers of iron status and sTfR. Iron deficient patients were treated with ferrous sulfate for 6 weeks, followed by repeat testing. RESULTS: At baseline, there was stronger correlation between sTfR and markers of hemolysis and erythropoietic drive, including hemoglobin (Spearman's r = -0.67, P < or = 0.001) and reticulocyte count (Spearman's r = 0.59, P < or = 0.001), than with markers of iron metabolism, such as transferrin saturation (TS; Spearman's r = 0.33, P = 0.02) and ferritin (Spearman's r = 0.17, P = 0.26). Eleven (21%) of the 51 children were identified as iron deficient. For treated patients, response to iron therapy was variable, although all patients had a significant increase (mean 11 +/- 3.9%, P = 0.001) in TS. CONCLUSIONS: sTfR activity is a stronger biomarker of hemolysis and erythropoietic drive than of iron-restricted erythropoiesis in pediatric SCD. Low TS was most suggestive of iron deficiency and an increase in TS represented the most consistent indicator of response to iron supplementation.