We studied the ability of B-lymphocytes to differentiate to immunoglobulin-producing cells in 14 patients with thalassemia major, 11 parents of the patients, and 86 normal subjects. In comparison with the parents of the patients and with the normal individuals, the patients were found to have 1) an increased number of cells spontaneously secreting immunoglobulin; 2) a decreased number of plaque-forming cells (PFC) when induced with pokeweed mitogen (PWM) and a deficient helper T-cell function for the induction of B-cell differentiation; 3) an increase in the number of PFC after the addition of alpha interferon (100 IU/ml) to the cell cultures with PWM. Previous incubation of non-T-cells with alpha interferon for 1 hr and subsequent coculture with T-cells from the same patients or from normal subjects in the presence of PWM increased the number of PFC. On the contrary, previous incubation of T-cells with alpha interferon followed by coculture with normal non-T-cells or cells from the same patient did not modify the number of PFC. These results suggest that patients with thalassemia major possess hyperreactive spontaneous B-cell responses and that these B-cells are unable to differentiate to immunoglobulin-secreting cells in the presence of PWM. This would be due to a T-helper-cell deficiency with an inability to produce lymphokines (interferon being one of them), while the B-cell function seems to remain intrinsically intact.