Purpose To conduct a multi-institutional, multireader study to compare the performance of digital tomosynthesis, dual-energy (DE) imaging, and conventional chest radiography for pulmonary nodule detection and management. Materials and Methods In this binational, institutional review board-approved, HIPAA-compliant prospective study, 158 subjects (43 subjects with normal findings) were enrolled at four institutions. Informed consent was obtained prior to enrollment. Subjects underwent chest computed tomography (CT) and imaging with conventional chest radiography (posteroanterior and lateral), DE imaging, and tomosynthesis with a flat-panel imaging device. Three experienced thoracic radiologists identified true locations of nodules (n = 516, 3-20-mm diameters) with CT and recommended case management by using Fleischner Society guidelines. Five other radiologists marked nodules and indicated case management by using images from conventional chest radiography, conventional chest radiography plus DE imaging, tomosynthesis, and tomosynthesis plus DE imaging. Sensitivity, specificity, and overall accuracy were measured by using the free-response receiver operating characteristic method and the receiver operating characteristic method for nodule detection and case management, respectively. Results were further analyzed according to nodule diameter categories (3-4 mm, >4 mm to 6 mm, >6 mm to 8 mm, and >8 mm to 20 mm). Results Maximum lesion localization fraction was higher for tomosynthesis than for conventional chest radiography in all nodule size categories (3.55-fold for all nodules, P < .001; 95% confidence interval [CI]: 2.96, 4.15). Case-level sensitivity was higher with tomosynthesis than with conventional chest radiography for all nodules (1.49-fold, P < .001; 95% CI: 1.25, 1.73). Case management decisions showed better overall accuracy with tomosynthesis than with conventional chest radiography, as given by the area under the receiver operating characteristic curve (1.23-fold, P < .001; 95% CI: 1.15, 1.32). There were no differences in any specificity measures. DE imaging did not significantly affect nodule detection when paired with either conventional chest radiography or tomosynthesis. Conclusion Tomosynthesis outperformed conventional chest radiography for lung nodule detection and determination of case management; DE imaging did not show significant differences over conventional chest radiography or tomosynthesis alone. These findings indicate performance likely achievable with a range of reader expertise. © RSNA, 2016 Online supplemental material is available for this article.