The clinic presentation and response to therapy in cutaneous leishmaniasis (CL) due to Leishmania (Viannia) braziliensis is quite variable. Comorbidities may be associated to atypical lesions as flat, superficial ulcers with not well- defined borders, large and ugly ulcers, multiple nodules localized in one segment of the body, exuberant exophytic lesions or hypertrophic ulcers. Here we describe how diabetes melittus, pregnancy and obesity may modify the clinic presentation of CL, the abnormalities in immunologic response responsible for these modifications and how comorbidities increase the rate of therapeutic failure to meglumine antimoniate therapy. Pregnancy is not a morbidity but as the fetus has about half of the antigens from the father it is important that pregnant women develop mechanisms to avoid fetus rejection. Some pregnant women may present typical CL ulcers, but some present exophytic lesions. Compared to non-pregnant women who have an inflammatory reaction mediated mainly by CD4+T cells expressing IFN-γ and macrophages, pregnant women have a more intense inflammatory reaction and CD4+ T cells expressing IL-4 is the predominant cellular type in the lesion. The diabetes mellitus impairs the immune response to bacteria and fungi mainly due to impair the ability of neutrophils to kill infectious agents. The leishmaniasis are protozoa caused diseases and the defense mechanisms is mediated by macrophages activated by CD4+ Th1 cells. We compare the clinic presentation of CL in patients with and without diabetes and we found that about 40% of the patients with diabetes and CL presents atypical lesions, mainly characterized by flat ulcers without defined borders, what is quite different from the classical well limited ulcers with raised borders observed in the majority of CL patients. While there was no difference in the production of IFN-γ between the 2 groups, patients with atypical ulcers produce higher levels of IL-1β, IL-6 and TNF than CL patients without diabetes. While there was no difference in the response to therapy comparing CL with diabetes versus those without diabetes, the cure rate in diabetic patients with atypical lesions was 33% while in diabetics with typical CL lesions was 81% (P<.05). Obesity is on rise in the whole world and obesity has been observed in the poorer population like people that live in endemic areas of leishmaniasis. In the endemic area of Corte de Pedra the prevalence of obesity is 18% and of overweight is 21%. Obesity may present atypical lesions characterized by hypertrophic ulcers predominantly above the belt. We have not found differences in the production of cytokines in obese and lean CL patients, but the cellular infiltrate is more intense in obese and in these patients the adipose tissue is infiltrated by neutrophils, macrophages and lymphocytes and phagocytosis and destruction of adipocytes are observed. Moreover, adipose CL produce higher leptin levels and have more neutrophils in the tissue than lean CL patients. The cellular infiltrate in the tissue is greater in obese than in CL, have more neutrophils and killing of adipocytes are documented the adipose tissue. Moreover, while the cure with meglumine antimoniate in lean CL patients is observed in up to 73%, in obese only 19% are cured with one course of antimony therapy. Different inflammatory pathways participate in the ulcer development of CL and obese, diabetics and pregnant women present different clinical presentation and poor response to therapy with meglumine antimoniate therapy.