<title>Abstract</title> <bold>Background:</bold> Co-infections associated with Immune Reconstitution Inflammatory Syndrome (IRIS) have been described in literature, however they constitute an uncommon finding in the medical community. <bold>Case presentation:</bold> Here we report a rare case of a 55-year-old woman from Cuba with prior medical history of HIV/AIDS adherent to her Highly active antiretroviral therapy (HAART) regimen, who was hospitalized in Miami 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 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. <bold>Conclusion: </bold>This case highlights the complexities and challenges in managing opportunistic infections during immune recovery in HIV/AIDS patients on HAART, and emphasizes the necessity of continuous vigilant monitoring and having a broad differential diagnosis in this group of patients.