The identity and functions of surface proteins on human leptomeningeal and meningioma cells are incompletely characterized. Some structural and functional similarities between the leptomeninges and pleura suggest that proteins important to pleural function and tumorigenesis might also be relevant to leptomeningeal disease. Mesothelin is a recently described, 40-kDa membrane protein expressed in pleura. Its functions in this tissue are under investigation. Sections of 20 normal adult brains with leptomeninges and 49 World Health Organization (WHO) grade I, 21 grade II, and 2 grade III meningiomas were analyzed using an extensively characterized monoclonal antibody to mesothelin and streptavidin-biotin complex immunohistochemistry. Five meningiomas were also evaluated by Western blot. Mesothelin immunoreactivity was detected in the arachnoid in 6 of 20 cases and in 23 of 49 WHO grade I meningiomas. It was also detected in 7 of 21 WHO II tumors and 1 of the 2 anaplastic meningiomas. By Western blot, all five meningiomas exhibited mesothelin precursor protein, including one where notable immunoreactivity was not identified in a formalin-fixed tissue section. These findings suggest that mesothelin is expressed in at least some arachnoid and meningioma cells. Future studies may clarify its role in the development of meningiomas, meningeal seeding of gliomas, and metastases to the leptomeninges.