For carcinoma specimens with non-grossly identifiable lesions such as microcalcifications, difficulties may be encountered in locating these abnormalities and sampling the margins that are at risk. This is magnified in the case of skin-sparing procedures where the margin is a much greater surface area and is the operation of choice in patients with diffuse microcalcifications and/or multifocal in situ disease. The objective of this study was to determine the efficacy of specimen radiographs of mastectomy in identifying occult carcinoma associated with microcalcifications and assessing the resection margins. We reviewed the histology and corresponding specimen radiographs of 16 patients with diffuse and widespread microcalcifications and who underwent skin-sparing mastectomy. After the specimens were serially sectioned, specimen radiographs of each section of the specimens were obtained with digital mammography equipment. Findings in the specimen radiographs were used to direct the histologic sampling of the specimens. On gross examination, two (12.5%) mastectomy specimens had identifiable discreet masses; the lesions were 4 and 7 mm, respectively. Histologic examination revealed the presence of carcinoma in 13 (81%) cases; seven with both infiltrating and in situ carcinoma and six with in situ carcinoma alone. The remaining three patients demonstrated only changes of biopsy site without any residual carcinoma. Microcalcifications were associated with in situ carcinoma in all malignant cases. Among the 12 cases with microcalcifications present at or within 2 mm of the margins, in situ carcinoma was present at the margins in three cases and located within 2 mm of the margins in two cases. All margins were negative in all cases with microcalcifications that were at least 1 cm away from the resection margins. The average number of tissue blocks examined was 16.6 ± 5.4. The average number of tissue blocks sampled among randomly selected mastectomy specimens was 15.2 ± 5.4. There was no statistically significant difference in the number of blocks between mastectomy cases with specimen radiographs taken and those without (t-test). Our study suggests that specimen radiographs may assist in identifying occult breast carcinoma associated with microcalcifications and assessing the resection margins without increased sampling. © 2009 Wiley Periodicals, Inc.