Immune Reconstitution Inflammatory Syndromes (IRIS) are exaggerated pathological inflammatory reactions occurring after initiation of highly active antiretroviral therapy (HAART) due to exuberant immune responses to occult or apparent opportunistic infections or cancers. In view of paucity of studies from Nigeria, we report 3 cases of IRIS presenting as disseminated infections in HIV-1 infected patients initiating HAART. The first case was a previously healthy female who developed disseminated tuberculosis after 4 weeks of regular HAART. Her HAART regimen was continued and she improved after commencement of anti-tuberculosis drugs, with evidence of progressive increase in CD4 cell count. The second case was a HAART-experienced female who stopped her drugs for 4 months. Two months after recommencement of her previous HAART regimen, she developed features of disseminated herpes zoster infection, despite evidence of decrease in viral load by 95%. HAART was continued and she recovered completely after receiving valaciclovir tablets and antibiotics. The third patient was a female student who was commenced HAART on account of chronic cough and weight loss. Three months after regular HAART, she developed features of disseminated Kaposi's sarcoma involving the skin, oropharynx and lungs, despite evidence of 42% increase in CD4 cell count. Unfortunately, she rapidly deteriorated and died during the course of management. Clinicians should be alert to the possibility of IRIS in HIV-infected patients initiated or re-initiated on HAART. There is need for future prospective studies determining risk factors for IRIS in HIV-infected patients from Nigeria.