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The purpose of this study was to evaluate the effect of independent reading with computer-aided diagnosis (CAD) and independent double reading on radiologists' performance to characterize mass lesions on serial mammograms. Six radiologists rated 198 cases, 99 benign and 99 malignant. For each case, the mammograms from two consecutive screening rounds were available. The mass was visible on the prior view in 40% of the cases. Independently, a CAD programe also rated each mass lesion making use of information from prior and current views. The following reading situations were compared: single reading, independent reading with CAD, and independent double reading. Independent reading with CAD was implemented by averaging the scaled ratings from each radiologist and the scaled CAD scores. We implemented independent double reading by averaging the scaled scores from two radiologists. Results were evaluated using receiver-operating characteristic (ROC) methodology and multiple reader multiple case analysis. The average performance, measured as the area under the ROC curve (Az value), was 0.80 for the single-reading mode. For independent double reading, the average performance improved to 0.81. This improvement was not significant. For independent interpretation with CAD, the average performance significantly increased to 0.83 (P < 0.05). We conclude that CAD technology with temporal analysis has the potential to help radiologists with the task of discriminating between benign and malignant masses.