Leishmaniasis is a worldwide disease, but due to the absence of surveillance systems is under-reported from low- and middle-income countries. In Ethiopia, the disease is found in the rural highlands and the incidence of Leishmania/HIV co-infection is increasing. Although some studies have been carried out in areas of the country with a similar disease/ecological profile this report is, to our knowledge, the first aimed at elucidating the clinical-epidemiological features of cutaneous and mucocutaneous leishmaniasis in Tigray, northern Ethiopia. This study enrolled 167 patients presenting different forms of cutaneous leishmaniasis over an 18 month period, of which 5.6% tested HIV positive. Patients were initially treated with meglumine antimonate and resistant cases with pentamidine isethionate. There was a high rate of resistance to meglumine antimonate (28%) and a less than optimal response to prolonged systemic treatment in relapsed cases. Eight patients affected by severe and resistant forms were treated with pentamidine isethionate, with a cure rate of 87.5% after 6 months. Many atypical and severe presentations were seen, and a poor response to first-line antileishmanial drugs was observed. Resistance to antimonials is of concern and cost-effective therapeutic schemes need to be developed. The cost-effectiveness of pentamidine isethionate has to be determined in a larger population.