Fibrosing mediastinitis (FM) is a rare disorder characterized by the invasive proliferation of fibrous tissue within the mediastinum. FM frequently results in the compression of vital mediastinal structures and has been associated with substantial morbidity and mortality. Its pathogenesis remains unknown. However, in North America most cases are thought to represent an immune-mediated hypersensitivity response to Histoplasma capsulatum infection. To characterize the clinical disease spectrum, natural disease progression, responses to therapy, and overall survival, we retrospectively analyzed all 80 consecutive patients with a diagnosis of FM evaluated at Mayo Clinic, Rochester, MN, from 1998 to 2007. Furthermore, we characterized the adaptive immune response in 15 representative patients by immunohistochemistry. The majority of patients presented with nonspecific respiratory symptoms due to the compression of mediastinal broncho-vascular structures. Chest radiographic imaging most frequently revealed localized, invasive, and frequently calcified right-sided mediastinal masses. Most patients had radiographic or serologic evidence of previous histoplasmosis. In contrast to earlier reports summarizing previously reported FM cases, the clinical course of our patients appeared to be more benign and less progressive. The overall survival was similar to that of age-matched controls. There were only 5 deaths, 2 of which were attributed to FM. These differences may reflect publication bias associated with the preferential reporting of more severely affected FM patients in the medical literature, as well as the more inclusive case definition used in our consecutive case series. Surgical and nonsurgical interventions effectively relieved symptoms caused by the compression of mediastinal vascular structures in these carefully selected patients. In contrast, antifungal and antiinflammatory agents appeared ineffective. Histologic examination and immunostaining revealed mixed inflammatory infiltrates consistent with a fibroinflammatory tissue response in these histoplasmosis-associated FM cases. The immune cell infiltrates included large numbers of CD20-positive B lymphocytes. As B lymphocytes may contribute to the pathogenesis of the disease, therapeutic B-cell depletion should be investigated as a therapeutic strategy for FM.