Introduction: Microcalcifications which do not belong to focal lesions are a difficult diagnostic problem to solve with mammography. We investigated the yield of 99mTc-Sestamibi (MIBI) scintigraphy in the assessment of the benign or malignant nature of these lesions and compared nuclear medicine with histologic and immuno-histochemical findings., Material and Methods: Twenty-seven areas of microcalcifications (0.3-5 cm in largest diameter) were considered; no solid masses or cysts were detected by mammography and sonography. The mammographic features of these microcalcifications were suggestive of malignancy in 3 cases and of benignity in 14; the diagnosis was questionable in the other 10 cases. MIBI scintigraphy was considered positive for malignancy when there was tracer uptake in the breast. Cytologic samples of all lesions were obtained with fine-needle aspiration under stereotactic guidance. Histology was performed in the 13 lesions considered malignant or dubious at mammography, independent of their cytology; histology was combined with immunohistochemical tests to assess intracellular mitochondria count and the number of vessels. The other 14 lesions, which were benign at mammography and cytology, were followed-up yearly for two years, and no change in clinical or radiological findings was demonstrated., Results: Histology diagnosed 8 ductal carcinomas (3 invasive carcinomas and 5 carcinomas in situ) and 5 benign lesions (1 sclerosing adenosis and 4 fibrocystic diseases, 3 of them associated with ductal hyperplasia). Scintigraphy was positive in 4/8 malignant lesions (3/3 invasive carcinomas, 1-3.5 cm in largest diameter; 1/5 carcinomas in situ, 5 cm in largest diameter) and negative in 4/5 benign lesions (we had one false positive in a fibrocystic disease associated with ductal hyperplasia). Tracer uptake was observed in all lesions with a high intracellular mitochondria count, except for 2 carcinomas in situ (0.3 and 0.8 cm in largest diameter, respectively); no benign or malignant lesion was well vascularized. Scintigraphy was negative also in the other 14 benign lesions with no histology., Conclusions: 99mTc-MIBI scintigraphy was able to characterize both invasive ductal carcinomas and benign lesions, which results hold even though our series was small because of the selection criteria we used. Thus, all invasive ductal carcinomas were identified and we had only one false positive (1/19) in benign lesions. In contrast, the technique was inadequate in carcinomas in situ, probably because their size and biological patterns vary greatly. Thus, scintigraphy was negative in 4/5 lesions (all < 1 cm O) and positive in only 1/5 (5 cm O). Therefore we conclude that 99mTc-MIBI scintigraphy cannot replace stereotactically-guided fine-needle aspiration in breast microcalcifications with questionable mammographic findings.