The purpose of this investigation was to determine the natural history and risk of malignancy associated with isolated indeterminate microcalcifications subjected to interval follow-up. During a 2-year study, 91 patients were identified with indeterminate microcalcifications alone. Specific roentgenographic features of the calcifications were evaluated on initial and follow-up mammograms. During a mean follow-up of 36 months, 19 (21%) of the women exhibited mammographic changes. Ten patients (11%) with suspicious changes underwent a needle-directed biopsy 6 to 30 months after the initial mammographic screening. Five women (5.5%) were diagnosed as having breast carcinoma; three had invasive ductal carcinoma and two had purely intraductal lesions. Four patients had axillary lymph node dissections and no metastatic disease was found. We found no significant differences in the roentgenographic features associated with malignant vs benign lesions apart from an increased overall estimation of the probability of malignancy rating in the five patients with breast carcinoma. We recommend that patients be followed up with mammography at regular intervals for at least 18 months following recognition of indeterminate microcalcifications.