In acquired immunodeficiency syndrome (AIDS) patients, immune reconstitution inflammatory syndrome (IRIS) due to Mycobacterium avium complex (MAC) infection is one of the most difficult IRIS types to manage. We report an unusual case of MAC-associated IRIS. At first the patient was diagnosed human immunodeficiency virus (HIV) infection after he was admitted with pneumocystis pneumonia. After starting antiretroviral therapy he presented unmasked IRIS with MAC infection. Next, he was hospitalized with continuous loose stools and new-onset fever. Investigation included computed tomography (CT), which showed homogeneous enhancement and enlargement of the lymph nodes (LN), elevation of ferritin (>1,650 ng/mL) and lactate dehydrogenase (306 IU/L) levels, and F- fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) scan, which showed increased FDG uptake. These findings were highly indicative of lymphoma. We performed laparoscopic biopsy of the mesenteric LN, and the biopsy culture grew MAC. So we made a diagnosis of MAC-associated. Therefore, IRIS must be considered as a possible diagnosis when AIDS patients develop new symptoms or exhibit exacerbations of existing symptoms. Furthermore the biopsies should be conducted.