Cryptococcosis is an opportunistic fungal infection found in both immunocompromised and non-immunocompromised patients; however, it is particularly prevalent in those with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS). Patients with isolated pulmonary cryptococcosis can present with heterogeneous symptoms. The rarity of this entity makes it difficult to recognize and diagnose. We present a case of a 54-year-old female with poorly controlled HIV and seizure disorder, who presented with suspected seizures. Her CD4 count was 7. Due to fever and headache, cryptococcal meningitis was suspected, and she was empirically started on liposomal amphotericin and flucytosine. Computed tomography (CT) of the head was negative for any acute intracranial process. Serum cryptococcal antigen was positive; however cerebrospinal fluid (CSF) studies from lumbar puncture (LP) were entirely negative, including CSF cryptococcal antigen. CT thorax demonstrated interval development of two solid pulmonary nodules in the right upper lobe (RUL). There was no other evidence of disseminated cryptococcal disease. CT-guided biopsy of the larger RUL was compatible with Cryptococcus species. Fungal cultures of sputum and blood were negative. The patient improved, and therapy was de-escalated from liposomal amphotericin and flucytosine to oral fluconazole, with a plan to complete a six- to twelve-month course of therapy. This case illustrates that in rare cases, Cryptococcal disease may still be localized despite having a positive serum Cryptococcal antigen. It also emphasizes the importance of a thorough investigation with multimodal diagnostic tools to evaluate for disseminated Cryptococcal disease, especially in those with a history of immunocompromise.Copyright © 2020, Dbaibou et al.