Leishmania skin test (LST) evaluates the delayed type hypersensitivity to Leishmania antigens (LA) and has been used for diagnosis of cutaneous leishmaniasis (CL). CL patients usually present a positive LST, but as small percentage have a negative LST (LST-). The aim of this study was to determine the clinic and immunologic features and response to antimony therapy in LST- CL patients. Methods. We compare the clinical presentation, response to therapy, and immune response of CL patients with negative vs positive LST. Results. The clinical presentation was similar in both groups but LST-negative patients had a lower cure rate. In the lesions, LST-negative patients displayed less inflammation and necrosis, and higher frequency of CD8+ T cells. Mononuclear cells from LST-negative patients had a poor T helper 1 cell (Th1) response but levels of interleukin-1β (IL-1β), IL-6, IL-17, granzyme B, and metalloproteinase-9 (MMP-9) were similar to the LST-positive group upon stimulation with LA. Leishmania internalization and killing by macrophages were similar in both groups. Cure of disease was associated with restoration of Th1 response. Conclusions. In LST-negative patients, impaired Th1 response is associated with therapeutic failure. Increased frequency of CD8+ T cells and high production of inflammatory cytokines, granzyme B, and MMP-9 contributes to immunopathology.