Introduction: Cryptococcus neoformans is a pathogenic yeast that is generally acquired by man from the environment via the respiratory route. Despite this route of acquisition, overt pulmonary infection is uncommonly diagnosed and the disease is usually manifest as a subacute meningitis which is mostly manifest in individuals who are celluarly immunoincompetent such as those on cancer chemotherapy, receiving anti-solid organ rejection medications and those with HIV/AIDS. Infection of the pleural space with C. neoformans is quite uncommon. We report a non-immunosuppressed man who was found to have infection of the pleural in the wake of bacterial empyema who was successfully treated with fluconazole. Case Report: A 66 year old man was referred to Infectious Diseases clinic in the wake of an admission for Streptococcus intermedius right sided thoracic empyema which was treated with appropriate antimicrobial therapy and chest tube drainage as well as a decortication of the right pleura. The pathology of the pleural peel showed acute and chronic inflammation and the pleural fluid and pleural tissue cultures were negative at the time of discharge. After discharge, the pleural peel culture grew C. neoformans and the patient was referred to ID. At the time of the visit, he complained as being generally fatigued but without fever, chills, sweats or cough. He also denied headache, stiff neck, nausea, vomiting or photophobia. A review of the pleural peel pathology showed no direct evidence of cryptococcosis. A serum cryptococcal antigen was ordered and he was begun on oral fluconazole for a planned 6 month course. The cryptococcal antigen was positive at 1:80 and serial assays performed during the treatment course. Date Serum Cryptococcal Antigen Aug2016 1:80 Sep2016 1:20 Dec2016 1:5 Jan2017 Non-reactive He remains asymptomatic following the therapeutic antifungal course. Conclusion: C. neoformans pleural peel infection was diagnosed from a pleural decortication procedure performed in the wake of S. intermedius bacterial empyema. Infections of the pleura or pleural space with Cryptococci are quite uncommon. The patient was successfully treated with fluconazole.