Midline destructive lesions have multiple possible etiologies, which can be grouped into neoplastic, infectious, or vasculitis-associated. The purpose of these case reports and literature review was to highlight the need to include mucocutaneous leishmaniasis in the diagnosis of midfacial lesions in any patient who has lived in Leishmania-endemic areas because this entity meets all of the clinical criteria to be considered a form of midline destructive lesion. We present two cases of mucocutaneous leishmaniasis that occurred in a Bolivian male immigrant and a European male traveler to Panama, in whom lesions were misdiagnosed as different midline destructive lesions with different causes (Wegener, vasculitis, and natural killer or T-cell lymphoma [NKTL]). The conclusion of our work is that all patients with midline destructive lesions should undergo histologic and molecular studies to be evaluated for mucosal leishmaniasis, particularly patients whose clinical history suggests this possibility. In cases of uvular involvement, biopsy of this region might be a possible alternative to nasal biopsy.