Highly active antiretroviral therapy (HAART) has dramatically decreased the incidence of HIV-1-associated morbidity and mortality. During the initial months of HAART, immune reconstitution inflammatory syndrome (IRIS), an adverse consequence of restoration of the pathogen-specific immune response, often occurred in terminal-stage in patients, with MAC infection the most frequently implicated in IRIS. In August 2004, a 26-year-old Japanese woman with fever and general lymphadenopathy was diagnosed with AIDS (HIV-1 RNA 5.7 x 10(5) copies/mL, CD4+ T cell count 10/microL) and disseminated Mycobacterium avium (M. avium) infection, for which antimycobacterial treatment was initiated. The M. avium infection responded well to two months of this treatment, and HAART was begun. Despite good virologic response to HAART (HIV-1 RNA <50 copies/mL), she contracted pulmonary disease with parenchymal lung changes, endobronchial lesions, and localized supraclavicular lymphadenitis, which are M. avium-associated IRIS. Good immunological response (CD4+ T cell count 136/microL) and a stronger antimycobacterial treatment helped her overcoming M. avium-associated IRIS without systemic corticosteroids or the discontinuation of HAART. The possibility of IRIS should always be watched for when treating AIDS patients with HAART and an antimycobacterial treatment regimen formulated that considers potential drug interactions with HAART.