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The first-line treatment for Leishmania donovani-induced cutaneous leishmaniasis (CL) in Sri Lanka is intra-lesional sodium stibogluconate (IL-SSG). Antimony failures in leishmaniasis is a challenge both at regional and global level, threatening the ongoing disease control efforts. There is a dearth of information on treatment failures to routine therapy in Sri Lanka, which hinders policy changes in therapeutics. Laboratory-confirmed CL patients (n = 201) who attended the District General Hospital Hambantota and Base Hospital Tangalle in southern Sri Lanka between 2016 and 2018 were included in a descriptive cohort study and followed up for three months to assess the treatment response of their lesions to IL-SSG. Treatment failure (TF) of total study population was 75.1% and the majority of them were >20 years (127/151,84%). Highest TF was seen in lesions on the trunk (16/18, 89%) while those on head and neck showed the least (31/44, 70%). Nodules were least responsive to therapy (27/31, 87.1%) unlike papules (28/44, 63.6%). Susceptibility to antimony therapy seemed age-dependant with treatment failure associated with factors such as time elapsed since onset to seeking treatment, number and site of the lesions. This is the first detailed study on characteristics of CL treatment failures in Sri Lanka. The findings highlight the need for in depth investigations on pathogenesis of TF and importance of reviewing existing treatment protocols to introduce more effective strategies. Such interventions would enable containment of the rapid spread of L.donovani infections in Sri Lanka that threatens the ongoing regional elimination drive. [ABSTRACT FROM AUTHOR]