Advanced HIV infection leads to profound immunosuppression and increased susceptibility to opportunistic infections. Resumption of antiretroviral therapy (ART) may result in immune reconstitution inflammatory syndrome (IRIS), which manifests as a worsening of an existing infection or the emergence of new ones. Disseminated mycobacteriosis caused by Mycobacterium avium complex (MAC) is one of the most severe opportunistic infections in the course of AIDS. The aim of this paper is to present the diagnostic and therapeutic difficulties in a AIDS patient who developed IRIS with generalized MAC infection and numerous metabolic and infectious complications following the resumption of ART, ultimately leading to treatment failure. We describe the case of a 34-year-old HIV-positive patient who had discontinued ART for several years. Clinical, laboratory, imaging, and psychiatric data collected during several months of hospitalization were analyzed. A multidisciplinary approach was employed, including antiretroviral, antimycobacterial, antifungal, nutritional, and psychiatric treatment. After ART was resumed, the patient developed IRIS in the form of disseminated MAC infection, confirmed in sputum, blood, and bone marrow. He developed refeeding syndrome, multidrug-resistant sepsis, and fungal and bacterial infections. Despite improved immunological parameters (increased CD4 and decreased HIV viral load), treatment was ineffective due to the patient's lack of compliance and worsening cachexia. This case illustrates the complexity of caring for patients with advanced AIDS and IRIS. Effective treatment requires a multidisciplinary approach, early diagnosis of IRIS, and consideration of psychosocial factors that can significantly complicate treatment and prognosis.