Cystoisospora belli causes intestinal infection in immunocompromised hosts, including human immunodeficiency viruses (HIV)-positive patients, especially from tropical and sub-tropical areas, with watery and recurrent diarrhea, leading in advanced cases to malabsorption and death. Microbiological diagnosis is limited by intermittent or low shedding of oocysts in stool; therefore, endoscopy may be necessary to identify the pathogen in histological samples. Trimethoprim-sulfamethoxazole (TMP-SMX) represents the treatment of choice, and alternative agents are used in recurrences, but limited efficacy is described. Here, we present recently observed case of severe and fatal infection due to C. belli in a HIV-positive 40-year-old man from Brazil, revealing several limitations in diagnosis and therapy, which need to be investigated further. In particular, it is still not clear how the infection persisted over time leading to malabsorption, kidney injury, and subsequent death, even if a reasonable immune reconstitution was demonstrated. Additionally, we investigated what mechanisms might cause, whether failure of recovery of the immune response specifically to C. belli, drug malabsorption, resistance to TMP-SMX, sequestration into lymphoid tissue, or co-presence of visceral untreated Kaposi sarcoma. Also, the appropriate dosage and way of administration of the best therapeutic regimen were examined, since there is a lack of literature on these issues. Globalization and wider use of immunosuppressive therapies underline the importance of maintaining adequate awareness, also in HIV-negative and non-immigrant populations.