Cryptococcus neoformans continues to present diagnostic and treatment challenges in patients with underlying malignant neoplasms. Cryptococcal empyema is a relatively rare complication of cryptococcal disease. It is important to distinguish whether uncontrolled malignancy or cryptococcal infection is responsible for the effusion. We used traditional diagnostic approaches, bronchoscopy and transthoracic fine needle aspiration, to verify the presence of the organism but continued to have treatment failure until adequate drainage was established.