Mammography remains the technique of choice for the detection of early breast cancer. The sensitivity of mammography is 85%, but is decreased in patients with dense breasts. Sestamibi scintimammography (SCM) has been suggested as an adjunctive modality to improve the detection of breast cancer. We conducted a study to determine the impact of SCM in patient management. A prospective study was conducted in 95 patients presenting with palpable masses and/or abnormal mammography scheduled for biopsy. Injection of 20-30 mCi of technetium-99m (Tc-99m) sestamibi into a pedal vein was performed. Ten-minute images of the breast and axilla were obtained in multiple projections. The mammography and SCM were correlated with pathology and clinical findings. The median age was 44 years (range 28-86 years). The total number of lesions was 104, as eight patients had bilateral lesions and one patient had two lesions in the same breast. Fifty-nine patients presented with palpable lesions and 45 patients with nonpalpable lesions (42 with abnormal mammography only and 3 with nipple discharge). A comparison of sensitivity, specificity, positive and negative predictive values, and overall accuracy of SCM and mammography were performed. The sensitivity and specificity for SCM were 83% and 83%, respectively, and for mammography were 65%, and 72%, respectively. The sensitivity and specificity for combined SCM and mammography were 87% and 94%, respectively. The p-value for mammography versus combined SCM and mammography was 0.0003 and that for SCM versus SCM and mammography was 0.0098. There were 80 (77%) benign and 24 (23%) malignant lesions. Of the 24 malignancies, SCM missed six (25%), versus eight (33%) by mammography. In two patients (9%) SCM detected malignancy in the breast that was not visualized by mammography or found on clinical examination. Sestamibi SCM improves the sensitivity of mammography and it detects up to 9% of malignancies not detected by mammography or clinical examination. This testing could impact the management of 16,500 patients in the United States every year. More studies are needed to better define its role in breast cancer detection.