A duropleural fistula is a pathologic communication between the central nervous system and the pleural space, permitting the abnormal passage and accumulation of cerebrospinal fluid within the pleural cavity. The etiology is diverse and includes iatrogenic, traumatic, and, less commonly, congenital or genetic causes. Clinical manifestations are often nonspecific, primarily due to the slow rate of cerebral spinal fluid production and accumulation, which may delay diagnosis if symptoms are not interpreted in the appropriate clinical context. Patients frequently present with progressive chest pain and dyspnea related to increasing pleural fluid volume. Thoracic discectomy and the creation of a ventriculopleural shunt are among the most common iatrogenic causes of duropleural fistula (DPF). Neurologic symptoms such as headache, altered mental status, and postural hypotension may accompany pulmonary manifestations and arise from disrupted cerebral spinal fluid dynamics within the low-pressure environment of the central nervous system. Computed tomography myelography is the diagnostic modality of choice when DPF is suspected, as it can precisely delineate the site of the fistulous communication. Pleural fluid analysis typically meets transudative criteria by Light’s classification; however, exudative characteristics may be observed in cases complicated by trauma, malignancy, or increased pleural vascularity. Detection of beta-2 transferrin, a protein found exclusively in CSF and perilymph, is highly specific and diagnostic for the presence of a DPF and should be assessed whenever clinical suspicion exists. Management strategies vary according to the etiology and severity of the fistula, ranging from conservative observation to definitive surgical repair of the dural–pleural tract. This chapter further explores the etiology, pathophysiology, clinicoradiologic and pathologic features, diagnostic approach, management strategies, and prognostic implications of duropleural fistula.