Primary pleuropulmonary meningothelial proliferations include minute pulmonary meningothelial-like nodules (MPMN) and pleural or pulmonary meningiomas (PPM). These lesions share histologic, ultrastructural, and immunohistochemical features with meningiomas of the central nervous system (CNS). Meningiomas of the CNS exhibit a number of genetic abnormalities, most commonly loss of the neurofibromatosis (NF) 2 gene on chromosome 22. The molecular changes of pleuropulmonary meningothelial proliferations, however, have only rarely been investigated. This study explores the status of the NF2 gene in pleuropulmonary meningothelial proliferations compared with CNS meningioma using interphase fluorescence in situ hybridization. Whole tissue sections of 9 pleuropulmonary meningothelial lesions (6 MPMNs and 3 PPMs) and 9 CNS meningiomas were analyzed by fluorescence in situ hybridization using a commercially available locus-specific probe for the NF2 region. Deletion of the NF2 gene was identified in 2 MPMNs, 1 PPM, and 4 CNS meningiomas. Chromosomal gains of 22q were noted in 2 cases of MPMN and 1 PPM. Our results indicate that pleuropulmonary meningothelial lesions share common genetic pathways with CNS meningiomas. In addition, they provide support for the hypothesis that MPMN and PPM are related lesions that may arise from the same precursor cell. As for CNS meningiomas, these mutational changes may provide additional targets for future personalized therapies.