Recognition that many patients with benign sclerosing mediastinitis have smoldering disease responsible for failure of surgical procedures or for development of collateral circulation in patients with superior vena caval obstruction has markedly improved management of these difficult patients. Histoplasmosis complement fixation titers have been used to detect unsuspected subacute disease and to follow the therapeutic adjunctive management with ketoconazole, an oral antifungal agent. Twenty-two patients with benign sclerosing mediastinitis demonstrated a variety of symptoms relating to the area of compression: superior vena cava, 13; esophagus, 3; pulmonary artery and pericardium, 3; and trachea, 3. Histoplasmosis was documented in 12 patients. Operation is used initially for diagnosis, to rule out carcinoma, and to treat the complications: superior vena caval reconstruction, 6; tracheal decompression, 2; right middle lobectomy, 1; esophageal decompression, 2; division of tracheoesophageal fistula, 1; and release of pericardial effusion and cardiac tamponade, 1. Postcardiotomy syndrome occurred in 1 patient and wound infection in another. No deaths resulted. In 6 cases of histoplasmosis, symptoms recurred in 100% of patients and were successfully managed with ketoconazole treatment, and then clinical progress was monitored with serial histoplasmosis complement fixation studies. One patient had four superior vena caval reconstructions at an outside hospital, each 1 year apart, with symptoms recurring each time. With ketoconazole therapy alone, she has been asymptomatic for more than 2 years. Vigorous search for a fungal cause may even obviate the necessity for surgical intervention. If an operation is necessary, preoperative and postoperative use of ketoconazole has assured success. © 1990.