Diabetes mellitus is one of the main endocrinological disease complicating the course of thalassemia major. This study aimed evaluate beta-cell secretion in 24 patients with thalassemia major attending the hematological Day Hospital at the Pediatric Clinic in Modena where transfusion therapy is performed in all thalassemic patients so as to maintain minimum hemoglobin levels above 10.5 g/dl, together with intensive ferrochelating therapy (desferrioxamine 50-60 mg/kg/die s.c. 6 days a week). A C peptide challenge with glucagon was performed in three patients already receiving insulin therapy for diabetes mellitus; this unexpectedly revealed a slight residual beta-cell secretion. An intravenous glucose tolerance test (IVGTT) was performed in the remaining 21 non-diabetic patients, with widely varying findings regarding insulin secretion: from below 50 microUl/ml in 5 patients to above 200 microUl/ml in 5 patients, and between 50 and 150 microUl/ml in the remaining 11 patients. This study therefore confirmed that insulin secretion frequently alters in thalassemic patients. Moreover, insulin secretion is not correlated to ferritinemia or influenced by familiar diabetes or patient age.