OBJECTIVE The objective of our study was to compare the effect of dual-energy subtraction and bone suppression software alone and in combination with computer-aided detection (CAD) on the performance of human observers in lung nodule detection. METHODS One hundred one patients with from one to five lung nodules measuring 5-29 mm and 42 subjects with no nodules were retrospectively selected and randomized. Three independent radiologists marked suspicious-appearing lesions on the original chest radiographs, dual-energy subtraction images, and bone-suppressed images before and after postprocessing with CAD. Marks of the observers and CAD marks were compared with CT as the reference standard. Data were analyzed using nonparametric tests and the jackknife alternative free-response receiver operating characteristic (JAFROC) method. RESULTS Using dual-energy subtraction alone (p = 0.0198) or CAD alone (p = 0.0095) improved the detection rate compared with using the original conventional chest radiograph. The combination of bone suppression and CAD provided the highest sensitivity (51.6%) and the original nonenhanced conventional chest radiograph alone provided the lowest (46.9%; p = 0.0049). Dual-energy subtraction and bone suppression provided the same false-positive (p = 0.2702) and true-positive (p = 0.8451) rates. Up to 22.9% of lesions were found only by the CAD program and were missed by the readers. JAFROC showed no difference in the performance between modalities (p = 0.2742-0.5442). CONCLUSIONS Dual-energy subtraction and the electronic bone suppression program used in this study provided similar detection rates for pulmonary nodules. Additionally, CAD alone or combined with bone suppression can significantly improve the sensitivity of human observers for pulmonary nodule detection.