OBJECTIVE Increased zinc protoporphyrin/heme (ZPP/H) ratio has been used in pediatrics to screen for iron deficiency and lead poisoning. This study was conducted to determine whether common hereditary hemoglobin disorders (alpha- and beta-thalassemia traits, hemoglobin E) found in U.S. minority groups are associated with an increase in the ZPP/H ratio in an iron-sufficient population. METHODS The database was compiled from hemoglobinopathy screens performed between 1987 and 1993 at a regional referral laboratory in Washington State. ZPP/H ratio and hemoglobin type were obtained for 326 subjects between the ages of 15 and 49 years of age who were iron sufficient (serum ferritin levels > or = 50 micrograms/L). RESULTS The mean ZPP/H ratio was significantly higher (p < 0.01) for subjects with beta-thalassemia trait (87 +/- 32 micromol/mol), (alpha-thalassemia trait (73 +/- 37 micromol/mol), and hemoglobin E disorders (73 +/- 24 micromol/mol) than for subjects with normal hemoglobin values (60 +/- 8 micromol/mol). Fifty-one percent of subjects with beta-thalassemia trait, 22% with hemoglobin E, and 20% with alpha-thalassemia trait had elevated ZPP/H ratios (> 80 micromol/mol), compared with only 1.5% with normal hemoglobin values. CONCLUSIONS The ZPP/H ratio is elevated in common hereditary hemoglobin disorders that mimic the microcytic anemia of iron deficiency, even in individuals without associated nutritional iron deficiency. For children who are treated for presumed iron deficiency, failure of the ZPP/H ratio to return to normal after adequate iron treatment, especially if microcytosis persists, indicates that a hereditary hemoglobin disorder may be present.