Persons with HIV infection have a higher risk of infectious pulmonary complications, chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis than individuals not infected with HIV. Herein, we describe the clinical course of a patient with longstanding and well-controlled HIV infection and multiple previous pneumothoraces who presented to medical attention with insidious onset of shortness of breath and was diagnosed with vanishing lung syndrome (VLS). The VLS or giant bullous emphysema is a distinct clinical syndrome characterized by large bullae, predominantly in the upper lobes, occupying at least one third of the hemithorax and compressing surrounding normal lung parenchyma. It is a progressive disorder that typically occurs in young men, the majority of whom are smokers. As people with HIV/AIDS are now surviving well into middle age and beyond, clinicians are more likely to encounter VLS and severe obstructive lung disease, which are potentially fatal but preventable conditions.