The leishmaniases comprise a group of diseases caused by infection by several species of intracellular protozoan parasites of the genus Leishmania, which are transmitted by the bite of an infected sandfly. The leishmaniases represent a global public health problem, affecting an estimated 12 million people around the world and ranging from self-healing skin lesions to potentially fatal systemic infections. Here, we use mouse models of CL and VL to investigate the effect of a host gene called UCP2. Uncoupling protein 2 (UCP2) is a mitochondrial carrier expressed in a wide variety of tissues, including white adipose tissue, skeletal muscle and the immune system. Intracellular pathogens such as Leishmania upregulate UCP2 and may weaken the immune system. Consequently, parasites survive and multiply within mouse macrophages. We demonstrate here that mice lacking the UCP2 gene are better able than WT mice to control both CL and VL. Infection was analyzed in vivo by measurement of footpad swelling, quantification of parasite load and assays for the production of cytokines and Leishmania-specific antibodies. These findings could have important implications in designing an effective approach to preventing leishmaniosis.