This study was performed to determine the clinical significance of diffuse dural enhancement (DDE) detected by magnetic resonance (MR) imaging and to typify enhancing patterns related to inflammatory or metastatic causes. The authors retrospectively evaluated the clinical, imaging, and laboratory characteristics of 20 consecutive patients with DDE. Those with DDE and an underlying neoplastic disease (13 patients) were compared to 11 consecutive patients with cytological evidence of neoplastic leptomeningeal metastasis evaluated by MR imaging. The DDE was often associated with an underlying malignancy (13 (65%) of 20 patients) but it coexisted with leptomeningeal metastasis in only one patient. Skull metastases were evident in 10 (77%) of 13 patients and cranial nerve palsies in six (46%) of 13. Other causes of DDE were related to cerebrospinal fluid (CSF) leak or shunting (five (25%) of 20), with or without symptoms of intracranial hypotension, and to dural sinus thrombosis and pachymeningitis. Dural biopsies obtained in two patients with DDE showed a narrow rim of granulation-like tissue adherent to the dural surface facing the inner skull table. Magnetic resonance subtraction, diffusion, and perfusion studies revealed unique characteristics in patients with metastatic causes as compared to those with DDE secondary to CSF leak. None of the patients with proven leptomeningeal metastasis had DDE, but four of them presented with focal dural enhancement and two displayed apparent leptomeningeal enhancement. The findings indicate that DDE is not a radiographic hallmark of leptomeningeal metastasis in spite of the similarities in clinical manifestations (for example, headache and cranial polyneuropathy). Nonetheless, DDE is most frequently associated with metastatic malignancies and particularly with skull metastases and CSF leak. Special MR techniques can discern the underlying cause and elucidate the disparity in the pathophysiological mechanisms leading to DDE.