To our knowledge, this is the first case report of a transudative pleural effusion with positive Cryptococcal antigen and culture. We describe a 32-year-old male with end-stage liver disease (ESLD) who presented to an outside hospital with dyspnea and a large pleural effusion. An initial pleural fluid analysis was positive for Cryptococcal Ag. However, the infection was eventually found to be widespread as he had positive Cryptococcal Ag and cultures in his pleural fluid, serum, and cerebrospinal fluid (CSF). His antimicrobial regiment was escalated from fluconazole to amphotericin B and flucytosine. His medical condition deteriorated, and the patient passed away. Due to its rarity and range of clinical severity, diagnosis of disseminated Cryptococcosis can be delayed. We present this case to bring awareness of this diagnosis as a differential in immunocompromised patients regardless of a transudative pleural effusion.