Serum erythropoietin (EPO) levels were determined by radioimmunoassay in 37 beta-thalassemia patients, the phenotype being thalassemia major (TM) in 30 and thalassemia intermedia (TI) in 7. The control group consisted of 37 healthy children. The mean serum EPO levels were significantly higher in patients with both TM (215.1 +/- 144.5) and TI (53.8 +/- 40.2) compared with the control group (9.3 +/- 4.6). Although the mean hemoglobin (Hb) concentrations in the patients with TM and TI were similar (8.6 +/- 0.9 and 8.7 +/- 1.1, respectively), the mean serum EPO level was significantly higher in TM patients than the patients with TI (P < .01). This finding may indicate that some other factors contributing to the metabolic adaptation to low oxygen concentration or improvement of the tissue oxygenation are as effective as the Hb concentration in EPO production. It is also suggestive of the fact that some amount of tissue hypoxia cannot be prevented in spite of polytransfusion regimens in TM patients. Serum EPO levels of TM patients were not found to be age related or correlated with the mean pretransfusional Hb levels. In the TM patients, the serum EPO concentration was not consistently correlated with clinical signs of erythropoietic activity. This may be indicative of personal differences with respect to the sensitivities of erythroid precursors to the increasing EPO levels in TM patients.