From 1968 to 1983, 19 patients were treated at the Joint Center for Radiation Therapy for symptomatic mediastinal masses before a biopsy was obtained. This study evaluates the impact of radiation on the ability to establish a pathologic diagnosis and the results of subsequent empirical therapy if no diagnosis was established. Eight of the 19 (42%) patients were not able to have a histologic diagnosis established at the time of biopsy. Seven of these eight patients went on to receive empiric therapy for what was thought to be the most likely diagnosis on clinical grounds. Four of the seven have not relapsed; three who have relapsed were found to have the diagnosis for which they were empirically treated. The untreated patient relapsed with seminoma. Thus, the use of emergency irradiation for mediastinal masses is sometimes associated with the loss of pathologic diagnosis. These patients likely have a radioresponsive disease (ie, lymphoma or seminoma) that may be treated successfully on the presumed clinical diagnosis even when the histologic diagnosis is lost secondary to prebiopsy irradiation.