A 26-year-old man with newly diagnosed advanced HIV infection developed rapid neurological deterioration shortly after initiation of antiretroviral therapy (ART). Neurodevelopmental examinations revealed a necrotic mass lesion in the central nervous system with extensive edema and mass effect. Serological tests confirmed previous exposure to Toxoplasma gondii and active Treponema pallidum infection. Despite extensive antimicrobial therapy, corticosteroids, and supportive care, the patient deteriorated clinically and died. Retrospective evaluation showed that this was immune reconstitution inflammatory syndrome (IRIS), probably due to central nervous system tuberculosis, with toxoplasmosis and syphilis as concomitant or confounding conditions. The case highlights the diagnostic complexity of IRIS in advanced HIV infection with multiple opportunistic infections.