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Miltefosine has been widely used against VL, but the emergence of resistant strains could impose a significant threat in the near future. The present study used high\u2010throughput proteomics to determine whether proteins are differentially expressed in miltefosine\u2010resistant (BHU875) and \u2010sensitive (DD8) <jats:italic>Leishmania\u00a0donovani<\/jats:italic> strains. Comparative proteomic analysis revealed up\u2010regulation of iron superoxide dismutase (FeSODA) in the resistant BHU875 strain compared to the drug\u2010sensitive DD8 strain. In accordance with the proteomic data, BHU875 showed higher FeSODA enzymatic activity relative to the sensitive strain. Molecular characterization of BHU875 parasites in which the gene encoding FeSODA was silenced demonstrated that drug sensitivity was restored and the intracellular survival of the parasite was lowered. This suggests that FeSODA activity plays a part in miltefosine resistance. 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