Background: Treatment failure of antimony drugs for anthroponotic cutaneous leishmaniasis (ACL) is rising. Recognizing predictive factors of unresponsiveness to treatment can substantially influence better ACL management. The goal of this study was to investigate predictive factors associated with treatment failure in ACL in Kerman, southeast Iran. Methods: This case-control study was conducted retrospectively on 2,128 ACL cases in Kerman over ten years from 2011 to 2020. The case group included patients whose lesions failed to resolve after one treatment course. The control group included those whose lesions were cured after one treatment course. Results: Treatment failure was observed in 13.5% of cases (10.7% of systemic therapy and 16.7% of local therapy). No significant difference was reported between the type of treatment and treatment failure. The association of treatment failure with winter-onset (P = 0.001, OR = 1.39, CI = 1.23–1.56), face (P = 0.001, OR = 1.86, CI = 1.38–2.49), ulceration (P = 0.01, OR = 0.51, CI = 0.30– 0.85), small diameter (P = 0.005, OR = 0.57, CI = 0.38-0.84) and long duration of lesions (P = 0.01, OR = 1.57, CI = 1.11–2.21) was validated by multivariate logistic regression analysis. Conclusion: Efficient detection and timely management of ACL cases are essential to reduce resistant cases, as lesions lasting longer than four months show poor response to treatment. Furthermore, early treatment of facial lesions with systemic therapy is suggested to optimize results and reduce the risk of disfiguring scars. Further surveys are required to determine the reason behind more treatment failure in winter-onset lesions.