Background: Cytokines and growth factors involved in the tissue inflammatory process influence the outcome of Leishmania infection. Insulin-like growth factor (IGF-I) constitutively present in the skin may participate in the inflammatory process and parasite-host interaction. Previous work has shown that preincubation of Leishmania (Leishmania) amazonensis with recombinant IGF-I induces accelerated lesion development. However, in human cutaneous leishmaniasis (CL) pathogenesis, it is more relevant to the persistent inflammatory process than progressive parasite proliferation. In this context, we aimed to investigate whether IGF-I was present in the CL lesions and if this factor may influence the lesions' development acting on parasite growth and/or on the inflammatory/healing process. Methodology. Fifty-one CL patients' skin lesion samples from endemic area of L. (Viannia) braziliensis infection were submitted to histopathological analysis and searched for Leishmania and IGF-I expression by immunohistochemistry. Results: In human CL lesions, IGF-I was observed preferentially in the late lesion (more than 90 days), and the percentage of positive area for IGF-I was positively correlated with duration of illness (r = 0.42, P < 0.05). IGF-I was highly expressed in the inflammatory infiltrate of CL lesions from patients evolving with good response to therapy (2.8% ± 2.1%; median = 2.1%; n = 18) than poor responders (1.3% ± 1.1%; median: 1.05%; n = 6; P < 0.05). Conclusions: It is the first time that IGF-I was detected in lesions of infectious cutaneous disease, specifically in American tegumentary leishmaniasis. IGF-I was related to chronicity and good response to treatment. We may relate this finding to the efficient anti-inflammatory response and the known action of IGF-I in wound repair. The present data highlight the importance of searching nonspecific factors besides adaptive immune elements in the study of leishmaniasis' pathogenesis.