Immune reconstitution inflammatory syndromes (IRISs) have been reported in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (AIDS) since the introduction of highly active antiretroviral therapy (HAART). This syndrome is characterized by clinical manifestations of opportunistic infections when signs of immune reconstitution are observed during therapy. We report on leishmaniasis, suggestive of HAART-induced IRIS, in 2 patients with AIDS. After beginning HAART, 1 patient presented with disseminated, tegumentary lesions, whereas the other patient's preexisting lesions worsened and became more extensive; however, at the same time, their CD4(+) T cell counts were recovering and their virus loads were decreasing significantly. The lesions healed with anti-Leishmania therapy.