Background: Hyperglycemia is known to increase phagocyte responsiveness, however immune cells from people with diabetes show inadequate antimicrobial functions. We recently show that aberrant production of leukotriene B4 (LTB4) is detrimental to host defense in experimental model of diabetes. Here, we will unveil the consequences of high glucose in the outcome of Leishmania braziliensis skin infection and determine the role of LTB4 in people with diabetes. Methods: Individuals with cutaneous leishmaniasis (CL), whether affected by diabetes or not, were recruited. Blood samples and lesion biopsies were harvested. Systemic levels of inflammatory mediators were measured in the plasma by ELISA, monocyte-derived macrophages were cultured, and lesion biopsies were destined for histopathological evaluation. After L. braziliensis infection of macrophages, the production of inflammatory mediators and Reactive Oxygen Species (ROS) were measured, along with the infection rate. Findings: We show that diabetes increases systemic levels of LTB4, IL-6 and TNF-α in CL. Only LTB4 correlated with blood glucose levels and healing time of CL in diabetes comorbidity. CL lesions of people with diabetes exhibit increased neutrophil and amastigote numbers. The macrophages of these individuals showed higher L. braziliensis loads, reduced production of ROS and unbalanced LTB4 /PGE2 ratio. Interpretation: Our data reveal an exacerbated systemic inflammation driven by diabetes during CL, in opposition to a local reduced capacity to resolve L. braziliensis infection, leading to a worse CL outcome. Funding Statement:This work was supported by Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB) [Grant number PET0009/2016]. Part of this study was financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (CAPES) Finance Code 001. Declaration of Interests: No conflict of interest was reported. Ethics Approval Statement: The Institutional Board for Ethics in Human Research at the Gonçalo Moniz Institute (Oswaldo Cruz Foundation-IGM-FIOCRUZ, Salvador, Bahia-Brazil), approved this study (protocol number: CAAE 95996618.8.0000.0040).