Different radiopharmaceuticals have been used to detect breast cancer. Among them, sestamibi has been extensively studied and has come to have a well-recognized role in the evaluation of palpable breast lesions. The goal of this study was to compare the diagnostic value of Tc-99m-labeled compounds, such as methylene diphosphonate (MDP) and pentavalent dimercaptosuccinic acid (DMSA-V), with sestamibi for palpable breast lesions, in the scope of a multicenter trial sponsored by the International Atomic Energy Agency. Methods: Patients from 7 countries were included: 47 women (mean age, 54 +/- 13 y) examined with MDP and sestamibi and 111 women (mean age, 55 +/- 12 y) examined with DMSA-V and sestamibi. Cancer was diagnosed in 41 of 49 lesions from the MDP group and in 78 of 113 lesions from the DMSA-V group. Axillary lymph node involvement was observed in 18 of 30 patients from the first group and in 27 of 53 patients from the second group. Prone scintimammography was performed using a dose of 740 MBq of each tracer, and diagnostic values were calculated from a masked interpretation of scans. Results: In the first group, the sensitivity for sestamibi and MDP studies was 82.9% and 65.9%, respectively, with a specificity of 87.5% and 50%, respectively. In the second group, the sensitivity for sestamibi and DMSA-N studies was 87.2% and 65.4%, respectively, with a specificity of 77.1% and 74.3%, respectively. Regarding axillary involvement, the sensitivity was 33.3% for sestamibi in both groups, whereas the values for MDP and DMSA-V were 16.7% and 7.4%, respectively. In contrast, the specificity for sestamibi was 83.3% and 92.3% for the first and second groups, respectively, and the specificity for MDP and DMSA-V was 91.7% and 100%, respectively. Conclusion: Sestamibi is the most adequate alternative among the mentioned Tc-99m-labeled radiopharmaceuticals for the evaluation of palpable breast lesions.