Leishmania (Viannia) braziliensis is the causative agent of cutaneous and mucosal leishmaniasis in South America, and the latter is a severe and disfiguring form of the disease. Our understanding of how L. braziliensis parasites interact with dendritic cells (DCs) is limited, partially due to the difficulty in generating axenic amastigotes. In this study, we successfully generated axenic amastigotes of L. braziliensis and used them to test the hypothesis that L. braziliensis infection efficiently triggers innate responses in DCs and the subsequent adaptive immune responses for parasite clearance. This study has revealed unique immunological features of L. braziliensis infection. Firstly, axenic amastigotes showed higher infectivity and the potential to stimulate C57BL/6 (B6) bone marrow-derived dendritic cells to produce IL-12p40 when compared with their promastigote counterparts. Both parasite-carrying and bystander DCs displayed an activated (CD11c(high)CD45RB(-)CD83(+)CD40(+)CD80(+)) phenotype. Secondly, L. braziliensis infection triggered transcription and phosphorylation of STAT molecules and IFN-stimulated gene 15 (ISG15). Finally, the self-healing of the infection in mice was correlated to the expansion of IFN-gamma- and IL-17-producing CD4(+) cells, suggesting the existence of active mechanisms to regulate local inflammation. Collectively, this study supports the view that innate responses at the DC level determine parasite-specific T cell responses and disease outcomes.