Abstract Background: The severity of clinical manifestations of cutaneous leishmaniasis can vary depending on factors such as the Leishmania species involved, the host’s species and their immune response, etc. This study was aimed to investigate the relationship between the severity of different clinical signs, histopathological changes, and genetic indicators, with Total Antioxidant Capacity in mice experimentally infected with Leishmania major. Materials and method: A total number of 105 eight-week-old BALB/c mice of both sexes were assigned to 7 experimental groups (15 in each) as follow: 1) Healthy mice, 2) Leishmania infected mice treated with 100 mg/kg/day, SC GlucantimeTM until complete healing, 3) Mice received 20 IU/kg/day of vitamin E, SC for 10 days to increase Total Antioxidant Capacity prior to infection and further treatment with Glucantime, 4) Leishmania infected mice received both vitamin E and Glucantime daily until complete healing, 5) Mice received 20 IU/kg/day of vitamin E, SC for 10 days, prior to infection, and 6) Leishmania infected mice received 20 IU/kg/day of vitamin E, SC up to the end of trial. 7) Mice received daily vitamin E until the end of the experiment. Assessment of wound size, pro-inflammatory (IFN-γ and TNF-α) and healing (KGF and EGF) genes expression, histopathological findings and mortality rate were done three times on days 31, 38 and 72 post-infection. Results: Approximately, 31 days after the parasite inoculation, dermal lesions were developed in all infected mice. In group 3, the clinical manifestations, healing time and histopathological changes were significantly more favorable, while, the group 4 showed the worst situation in terms of the evaluated indicators. Discussion and Conclusion: While the high level of Total Antioxidant Capacity before the onset of the disease has an effective role in the recovery indicators, its simultaneous elevation at the beginning of infection will decrease the body's ability to effectively
