AbstractLeprosy is a chronic infectious peripheral neuropathy that is caused by Mycobacterium leprae, and the skin is one of its preferred target sites. However, the effects of this infection on the skin microbiome remain largely unexplored. Here, we characterize and compare the lesional and non-lesional skin microbiomes of leprosy patients and healthy individuals through the deep sequencing of 16 S rRNA genes. Additionally, a subset of patients was monitored throughout the multi-drug therapy to investigate its effect on the leprous skin microbiome. Firmicutes-associated OTUs (primarily Staphylococcus) prevailed in healthy individuals. By contrast, Firmicutes was underrepresented and Proteobacteria was enriched in the patients’ skin, although a single dominant taxon has not been observed at a finer taxonomic resolution. These differences can be explained by the significant decrease in Staphylococcus and Streptococcus as well as the enrichment in Brevundimonas. The overrepresentation of Micrococcus in patients is also remarkable. Genus-level compositional profiles revealed no significant intrapersonal difference between lesional and non-lesional sites. Treatment-associated changes indicated a loss of diversity and a shift in the community composition, with stronger impacts on the OTUs that are considered indigenous bacteria. Therefore, the molecular signatures associated with leprosy identified herein might be of importance for early diagnostics.