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We report a case of immune reconstitution inflammatory syndrome (IRIS) in a 32-year-old man infected with human immunodeficiency virus and Leishmania guyanensis. Three months after initiation of highly active anti-retroviral therapy (HAART), the patient had disseminated cutaneous leishmaniasis and started anti-leishmanial therapy. The patient’s leishmaniasis manifestations during HAART ranged form an anergic response (46 CD4+ T cells/μL) to a disseminated cutaneous leishmaniasis (112 CD4+ T cells/μL). Eight weeks later (168 CD4+ T cells/μL, skin biopsy specimens showed inflammatory infiltrates with no detectable amastigotes. The patient then became comatose. Prednisone therapy (60 mg/day) was initiated with a significant improvement within 48 hours. Three months later (CD4+ T cell count = 184 cell/μL), localized, classic, cutaneous leishmaniasis developed in the patient and anti-leishmanial treatment was re-introduced. On that occasion, frequency of T regulatory cells was 1.82% of all CD4+ cells. Our data suggest a pivotal role for CD4+ T cells in the onset of IRIS and lesion ulceration and their association with a low frequency of T regulatory cells.