INTRODUCTION: Cutaneous leishmaniasis caused by L. tropica is common in the Middle East and treatment failure and drug resistance are known to occur. Several genetic mechanisms: aneuploidy, recombination and loss of heterozygosity, single nucleotide polymorphism (SNP) changes, copy number variation (CNV), and mutation of the H locus associated with drug resistance have been described. MATERIALS AND METHODS: We studied SNP and CNV patterns in 22 isolates of L. tropica from Afghanistan, Iran and Syria in a geographic, phylogenetic and antimony exposure context. RESULTS: A high SNP frequency was observed in isolates from Syria on chromosome 23, including the H locus, linked to different ancestry at that chromosome segment. Among the isolates from Afghanistan and Iran, an elevated frequency of nonsynonymous SNPs was observed on several chromosomes. Changes in CNV patterns were seen in isolates exposed to drug pressure, especially for the ferric iron reductase gene. Expanded genes were categorised into five functional categories: translational elongation, mitochondrial transmembrane transport, positive regulation of cellular component organisation, response to stimulus and response to hypoxia. No CNV was identified at the H locus, the MAPK1 gene, the APQ1 gene, nor chromosomes 23, 31 or 36 regardless of previous antimonial exposure. DISCUSSION: In our study, Leishmania tropica had a jump in the nonsynonymous SNP rates at chromosome 23, including the H locus. CNV was observed among isolates exposed to antimonials, especially involving the gene encoding a ferric iron reductase. Several essential genetic coping mechanisms in the cell were enhanced when exposed to antimony, possibly for the survival of the parasite. Our work supports the perspective that Leishmania uses several mechanisms to adapt to environmental changes and drug exposure.