The aim of the study is to compare independent double readings by radiologists and computer-aided diagnosis (CAD) in diagnostic interpretation of mammographic calcifications. Ten radiologists independently interpreted 104 mammograms containing clustered microcalcifications. Forty-six of these were malignant and 58 were benign at biopsy. Radiologists read the images with and without a computer aid by using a counterbalanced study design. Sensitivity and specificity were calculated from observer biopsy recommendations, and receiver operating characteristic (ROC) curves were computed from their diagnostic confidence ratings. Unaided double-reading sensitivity and specificity values were derived post hoc by using three different objective rules and an additional rule of simulated-optimal double reading that assumed that consultations for resolving two radiologists' different independent diagnoses always produce the correct clinical recommendation. ROC curves of unaided double readings were obtained according to the literature. Single reading without computer aid yielded 74% sensitivity and 32% specificity, whereas CAD reading yielded 87% sensitivity and 42% specificity and appeared on a higher ROC curve (P < .0001). Three methods of formulating independent double readings generated sensitivities between 59% and 89%, specificities between 50% and 13%, and operating points that moved essentially along the average unaided single-reading ROC curve. ROC curves of unaided independent double readings showed small, statistically insignificant improvement over those of unaided single readings. Results of the simulated-optimal double reading were similar to CAD: 89% sensitivity and 50% specificity. Independent double readings of mammographic calcifications may not improve diagnostic performance. CAD reading improves diagnostic performance to an extent approaching the maximum possible performance.