Restoration of the immune system after highly active antiretroviral therapy (HAART) resulting from a quantitative and qualitative process of cell immune activity recovery may evolve with adverse clinical phenomena, known as the immune reconstitution inflammatory syndrome (IRIS). It can occur in association with several opportunist infections, although most reported cases have been related to mycobacterial infection caused by Mycobacterium tuberculosis and Mycobacterium avium. We describe three clinical cases of mycobacterial infection with different presentation patterns of IRIS after HAART. In each of these patients, immune reconstitution led to clinical manifestation of a latent infection, or clinical worsening of preexisting lesions, or manifestation of new lesions in the central nervous system. Clinical aspects of IRIS are presented in the paper and clinical management options for this event are carefully discussed.