To investigate the relationships between mammographic calcifications and pathologic lesions, and to develop guidelines for specimen sampling, we prospectively studied 157 consecutive needle localization breast biopsies (NLBB) using a technique in which radiographic findings in sectioned specimens were correlated with the histologic findings. All NLBBs were performed because of mammographic microcalcifications without a soft tissue density, and macroscopic examination in each case failed to reveal a gross lesion. All specimens were submitted in their entirety. Microscopically, 32% of the cases showed carcinoma, 12% demonstrated atypical hyperplasia, and 56% consisted of benign breast tissue without atypia. Forty-nine of the 50 cancers (98%) and 14 of the 19 atypical hyperplasias (74%) were associated with the radiographic calcifications. If histologic examination had been restricted to areas of the specimens containing the radiographic microcalcifications and the remaining tissue submitted only for cases of carcinoma or atypical hyperplasia on the initial sections, 38% fewer tissue blocks would have been processed, but one case of noncomedo ductal carcinoma in situ and five cases of atypical hyperplasia would have gone undetected. If microscopic examination had also included all additional tissue consisting of fibrous parenchyma, all 50 carcinomas and 17 of the 19 atypical hyperplasias would have been detected and 20% fewer tissue blocks would have been submitted. We conclude that restricting histologic examination of NLBB to areas of radiographic calcifications and fibrous parenchyma results in a high level of detection of clinically significant lesions and a considerable reduction in the amount of tissue processed.