Leishmaniasis is an emerging disease in HIV-infected persons; visceral leishmaniasis is an AIDS-defining opportunistic infection. The parasite that causes this infection is usually transmitted by the sandfly and occasionally by nonsterile needles among intravenous drug users. Diffuse cutaneous leishmaniasis (DCL) is a rare anergic variant of leishmanial infection with the characteristic presentation of numerous nonulcerating nodules with an abundant parasite load, lack of visceral involvement, negative reaction to the leishmanin skin test, and a chronic course with incomplete response to treatment and frequent relapses. We report a case of DCL that developed in the context of the immune reconstitution inflammatory syndrome (IRIS) in a man with AIDS following initiation of antiretroviral therapy. We also review DCL to emphasize the importance of recognizing and treating this evolving disease in the growing population of patients on immunorestorative therapy.