It has been speculated that, as seen in tuberculosis, human immunodeficiency virus (HIV) and Mycobacterium leprae (M. leprae) co-infection may exacerbate the pathogenesis of leprosy lesions and/or lead to increased susceptibility to leprosy. However, to date, HIV infection has not appeared to increase susceptibility to leprosy. In contrast, initiation of antiretroviral treatment (ART) has been reported to be associated with anecdotal activation of M. leprae infection and exacerbation of existing leprosy lesions. To determine whether ART is associated with worsening of the manifestations of leprosy, a cohort of leprosy patients recruited between 1996 and 2006 at the Oswaldo Cruz Foundation (FIOCRUZ) Leprosy Outpatient Clinic in Rio de Janeiro, Brazil, was studied longitudinally. ART treatment of HIV/leprosy co-infection was associated with the tuberculoid type, paucibacillary disease, and lower bacillary loads. CD4 lymphocyte counts were higher among HIV/leprosy patients at the time of leprosy diagnosis, while viral loads were lower compared with the time of HIV diagnosis. The conclusion was that ART and immune reconstitution were critical factors driving the development and/or clinical appearance of leprosy lesions.