PURPOSE: We investigated whether the diagnostic performance of SPECT scintimammography (SMM) can be improved by adding computer-aided diagnosis (CAD) of ultrasonography (US). MATERIALS AND METHODS: We reviewed breast SPECT SMM images and corresponding US images from 40 patients with breast masses (21 malignant and 19 benign tumors). The quantitative data of SPECT SMM were obtained as the uptake ratio of lesion to contralateral normal breast. The morphologic features of the breast lesions on US were extracted and quantitated using the automated CAD software program. The diagnostic performance of SPECT SMM and CAD of US alone was determined using receiver operating characteristic (ROC) curve analysis. The best discriminating parameter (D-value) combining SPECT SMM and the CAD of US was created. The sensitivity, specificity and accuracy of combined two diagnostic modalities were compared to those of a single one. RESULTS: Both SPECT SMM and CAD of US showed a relatively good diagnostic performance (area under curve = 0.846 and 0.831, respectively). Combining the results of SPECT SMM and CAD of US resulted in improved diagnostic performance (area under curve =0.860), but there was no statistical differerence in sensitivity, specificity and accuracy between the combined method and a single modality. CONCLUSION: It seems that combining the results of SPECT SMM and CAD of breast US do not significantly improve the diagnostic performance for diagnosis of breast cancer, compared with that of SPECT SMM alone. However, SPECT SMM and CAD of US may complement each other in differential diagnosis of breast cancer.