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In this study, we described, for the first time, specific aspects of an anti- Leishmania immune response in a Brazilian Xakriabá indigenous community. Induction of an intracellular NO pathway, triggered by the binding of IgE to CD23 receptor in IFN- γ/ IL-4 cytokines environment, was evaluated in localized cutaneous leishmaniasis ( LCL) carriers and positive Montenegro skin test ( MST) individuals without skin lesion ( MT+ SL−). Our data demonstrated that the higher frequency of CD23+ CD14+ monocytes and the increased serum levels of IgE observed in the LCL group were even higher in LCL carriers with late lesions ( LCL≥60). Furthermore, patients with LCL presented increased NO production after Leishmania (Viannia) braziliensis stimulation and this NO profile was independent of the time of the lesion (recent LCL<60 or late LCL≥60). We also showed that the increased frequency of IFN-γ+ and IL-4+ CD4+ T cells is related to the MT+ SL− group. The results of biomarker signature curves demonstrated that in the MT+ SL− group, the index signature was characterized by DAF-2T+ CD14+/ IL-4+ CD8+/ IFN-γ+ CD4+/ IL-4+ CD4+. On the other hand, the LCL group presented a higher index of DAF-2T+ CD14+/ CD23+ CD14+/ IL-4+ CD8+, associated with a lower index of IFN-γ+ CD8+. Considering the time of lesion, data analysis demonstrated that the main differences observed were highlighted in LCL<60 patients, with a higher index of CD23+ CD14+, which was also present in LCL≥60 patients. In conclusion, our data suggest that the protective immune response involving CD23-IgE-mediated NO release is a hallmark of patients with LCL. However, in MT+ SL− individuals, another different leishmanicidal mechanism seems to be involved. [ABSTRACT FROM AUTHOR]