Background: In Iran, zoonotic and anthroponotic cutaneous leishmaniasis (CL) are caused by Leishmania major and L. tropica respectively. Despite extensive studies, no effective therapies have ever been reported for CL. The main objective of this research was to determine and compare the three different protocols for treatment of CL patients referring to Skin Diseases and Leishmaniasis Research Center (SDLRC), affiliated to Isfahan University of Medical Sciences, Isfahan, Iran from September 2017 to October 2018. Methods: In a randomized controlled parallel groups clinical trial, 150 selected CL patients who met our inclusion criteria were randomly assigned to one of the three therapy groups: A, intra-lesional glucantime plus 50% trichloroacetic acid (TCA), B, intralesional glucantime and C, systemic glucantime. All patients in the three groups received the complete course of treatment and were followed for 6 months. To identify the etiologic agents, smears from their lesions were prepared and PCR-RFLP was used after parasite culture. Also, clinical characteristics, history of previous involvement, endemic emigration and demographic data were collected. Results: The results showed that the mean value of healing period was 53.12 ± 25.88 (median: 45, IQR: Q1 = 30-Q3 = 77) days in group A, 57.22 ± 44.02 (median: 42.5, IQR: Q1 = 30-Q3 = 60) days in group B, and 73.56 ± 41.08 (median: 71, IQR: Q1 = 45-Q3 = 90) days in group C; the observed differences were statistically significant (P=0.024). There was a significant difference between group A and group C (P = 0.049), and between group B and group C (P = 0.047) in terms of mean healing period. Finally, complete recovery rates of 80%, 62% and 42% were shown in the three medicinal groups of A, B and C, respectively (P = 0.022). Conclusion: In this study, the average duration of lesion healing among the three groups was the shortest in patients with IL glucantime plus 50% TCA treatment regimen. Also, the use of 50% TCA in patients suffering from CL was associated with a significant improvement in the depth of scars, the time and the percentage of recovery, and the low cost of this agent in the treatment of CL.