T-cell clones capable of mounting a proliferative response to Mycobacterium leprae were obtained in three leprosy patients (two polar lepromatous and one polar tuberculoid) either from M. leprae-activated or from protein-purified derivative-activated polyclonal T lymphoblasts. All these clones expressed the CD4 surface marker. Some of them proliferated to the antigen only in the presence of interleukin-2. A majority expressed cross-reactive responses to other mycobacteria. Clones obtained from the lepromatous patients did not differ in any of these features from those obtained from the tuberculoid patient. M. leprae-reactive clones obtained from one lepromatous patient displayed strong antigen-specific cytotoxicity toward autologous antigen-coated target cells. This phenomenon was not observed for any clone of the other lepromatous patient and was seen only for one clone in the tuberculoid patient.