The objective of this study was to compare chest radiography with computed tomography (CT) in the prediction of a specific diagnosis in adult patients with anterior mediastinal masses. Chest radiographs and CT scans of 128 patients with anterior mediastinal masses were randomized and analyzed retrospectively by two independent observers. The observers listed the three most likely diagnoses in order of probability and recorded the degree of confidence in their first-choice diagnosis. Findings from chest radiographs and CT scans were recorded by each observer and used for a stepwise discriminant analysis between diagnoses. Results showed that the correct first-choice diagnosis, regardless of the degree of confidence, was made in 36% of chest radiographs and 48% of CT scans (p < 0.05). The correct diagnosis was included among top three diagnoses in 59% and 72% of the studies, respectively (p < 0.001). A high confidence diagnosis (level 1) was reached in 9% and 34% of each study, respectively, (p < 0.001), and was correct in 58% and 80% of the studies, respectively. Interobserver agreement (k statistics) on the correct first-choice diagnosis was 0.45 and 0.53, respectively. Interpretations of the CT scans were most often accurate in the confident diagnosis of benign germ cell tumors (n = 10, 100%), thymolipomas (n = 3, 100%), and omental hernia (n = 2, 100%). Seven of 15 radiographic findings and 11 of 22 CT findings were discriminant. We conclude that although CT is better then chest radiography in determining the pathologic diagnosis of an anterior mediastinal mass, CT is still poor at making that prediction with confidence. However, several anterior mediastinal masses could be diagnosed accurately by CT.