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Lepromatous leprosy patients generally have reduced response to Mycobacterium leprae antigens in an in vitro lymphocyte transformation test, which could be due to insufficient generation of reactions or to active suppression of any reaction generated. We could detect 3 types of lack of reactivity: one which could be restored by the addition of supernatants from healthy, PHA-stimulated lymphocyte cultures, one which could not thus be restored and one in which the culture supernatant contained factors able to suppress mitogen responses of healthy cells. We compared responses of cells rom untreated patients, patients treated for 12–20 months with multiple drug therapy and patients with up to 20 years of dapsone treatment; all types of the disease were represented. Untreated patients of all types had low responses which were not always reconstituted by lymphokine-rich supernatants, but they did not produce the non-specific soluble suppressive factors. In most cases, including BL/LL types, after the initial months of treatment, antigen response improved and was further increased by the addition of supernatants containing lymphokines. Most of the long-term-treated, stable patients had a lymphokine-reconstitutable antigen response, and in most cases also produced non-specific suppressive factor(s). The question as to why leprosy patients do not respond to M. leprae antigen is a complex one; our results suggest that it is related to the activity of the infection in each group of patients.