Abstract Background Co-infections associated with Immune Reconstitution Inflammatory Syndrome (IRIS) have been described in literature, however they constitute an uncommon finding in the medical community. Case presentation Here we report a rare case of a 55-year-old woman from Cuba with prior medical history of HIV/AIDS adherent to her antiretroviral therapy (ART) regimen, who was hospitalized in Miami, Florida because of fluid dysphagia, odynophagia and right-sided cervical lymphadenopathy. A prior biopsy of the right cervical lymph node performed in an outside hospital found evidence of non-caseating granulomas with budding yeast, which was later confirmed to be disseminated histoplasmosis by a positive (1-3) -β-glucan assay and histoplasmosis urine antigen in this admission. Furthermore, after multiple imaging testing due to her clinical condition, a brain MRI demonstrated findings concerning for cerebral toxoplasmosis, which was supported by serology findings. Treatment with liposomal amphotericin B and TMP-SMX led to clinical and radiological improvement of this patient’s conditions, and she was discharged with an appointment for follow-up in the clinic. Conclusion This case highlights the complexities and challenges in managing opportunistic infections (OIs) during immune recovery in HIV/AIDS patients on ART, and emphasizes the necessity of continuous, vigilant monitoring and having a broad differential diagnosis in this group of patients.