Th1-type cellular immune responses play a critical role in protection against infection with Leishmania parasites, whereas activation of Th2-type cells results in progressive disease. Cutaneous leishmaniasis caused by Leishmania major is often a self-healing disease; however, persistent nonhealing forms are also known. In the present study, we have described cell-mediated immune responses in nonhealing patients by measuring T-cell proliferation, cytokine production, and phenotypic characterization of these cells. The responses were compared with those of patients with active lesions, patients who had recovered from infection, and healthy controls. Peripheral blood mononuclear cells from patients with active lesions and recovered donors proliferated vigorously and produced Th1-type cytokine when stimulated with L. major antigens, whereas in nonhealing patients the proliferative responses were significantly lower and showed a Th2-type response to Leishmania antigens. Interleukin-10 (IL-10) production was not a feature of L. major stimulation. Flow cytometric analysis revealed that L. major antigen induced proliferation of the CD4-positive population and that these cells were the major source of gamma interferon and IL-4. These results show a distinct dichotomy in the cytokine response to L. major infection.Leishmania major is the causative agent of zoonotic cutaneous leishmaniasis (CL) and affects millions of people in many parts of the world (30). The disease is prevalent in many areas of Iran. Hyperendemic foci of zoonotic CL in northeastern, southwestern, and central parts of Iran have been reported (9, 10, 31). The most common presentation of CL is one or a few skin lesions, which often heal spontaneously and leave a depressive scar. However, a rare presentation of infection, involving persistent lesions, is also known. These so-called nonhealing forms last for several years and do not respond to conventional chemotherapies. Patients are mostly from areas of hyperendemic infection and include some of the soldiers who were immunized with virulent parasites (leishmanization) during the Iraq war against Iran. Some of these patients experience periods of remission and reactivation at the site of inoculation, and others suffer from chronic lesion for several years.Extensive studies with experimental models have shown that the outcome of infection is critically dependent on the activation of one of the two subsets of CD4 T cells, Th1 and Th2 (26). Gamma interferon (IFN-␥), secreted by Th1 cells, is the most potent macrophage-activating cytokine leading to host resistance to infection with Leishmania parasites (27, 29), whereas interleukin-4 (IL-4), secreted by Th2 cells, is associated with down-modulation of IFN-␥-mediated macrophage activation (1, 17). However, in human cutaneous leishmaniasis, a clear functional dichotomy in CD4 T cells has not definitely been documented. Concerning the key role of cytokines, we were interested in defining the immune response of nonhealing patients and comparing it with that of in...