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Leishmania (L.) infantum is the main causative agent of animal and human leishmaniasis in the Mediterranean basin. Despite its clinical significance, little is known on the genetic diversity of L. infantum parasites circulating in Italy. Here, we apply a comparative genomics approach on seven L. infantum isolates from different hosts (human, dog, cat, marten) and geographic regions (Emilia-Romagna, Sicily, Sardinia) as a first attempt to explore the breadth of parasite genetic heterogeneity in Italy. We revealed important genome instability at karyotype levels, with each isolate presenting a unique aneuploidy profile. Read depth analysis further identified strain-specific changes in gene dosage, which affected important virulence factors most of which are encoded by multi-copy gene arrays, such as amastins or surface antigen-like proteins. SNP-based clustering analysis of these genomes together with over 80 publicly available L. infantum and L. donovani genomes placed the Italian isolates into three geographically distinct clusters, with two isolates grouping with Spanish strains, two isolates grouping with Tunisian strains, and three isolates clustering with putative L. infantum/L. donovani hybrids isolated in Cyprus. As judged by microsatellite profiling of 73 isolates from dogs, sand flies and VL cases, these hybrid isolates are representative of a sub-population of parasites circulating in northeastern Italy that preferentially infects humans, but not dogs. In conclusion, our data uncover a remarkable heterogeneity of L. infantum isolates that indicates different geographic origin, including a novel hybrid-like genotype associated with an unusual infection pattern, placing Italy at the crossroad of Leishmania infection in the Mediterranean region.