A 31-year-old African American woman with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (recent CD4 count of 66/mm) presented to the emergency room with a tension pneumothorax that required an emergent chest tube placement. Computed tomography scan showed fungus balls in multiple lung cavities and surrounding infiltrates. The patient showed remarkable improvement with voriconazole suggesting aspergillosis. However, the patient was serologically negative for Aspergillus and other common fungal infections. Because of a persistent air leak, surgical intervention was needed. The histological finding was consistent with invasive mycosis, and cultures were positive for Scedosporium apiospermum. Literature review showed that, among patients with HIV/AIDS, Scedosporium can present from focal localized to systemic disease, is resistant to traditional antifungal agents, and may respond to prompt management with voriconazole.