Previous studies with 201Tl and 99mTc-sestamibi (MIBI) have used large field of view (LFOV) cameras not optimized for breast imaging. The purpose of this study was to compare these agents and to determine if a small field of view (SFOV) camera designed to minimize the camera-to-breast distance could improve tumor detection. METHODS A 28-cm (SFOV) camera was fitted with slant-hole and diverging collimators to perform craniocaudal scintigraphy for direct comparison with mammography. Of the 46 patients studied, 20 had 201Tl imaging alone and 26 had combined 201Tl and MIBI imaging. LFOV (40 cm) breast and axillary images also were obtained. Visual and quantitative analyses of tumor uptake were performed. RESULTS The SFOV camera with nonparallel collimation showed variable 201Tl and MIBI normal breast activity. This was partly due to significant scatter from cardiac and abdominal activity. Overall, 201Tl had a sensitivity of 53%, which was 67% for tumors > or = 1.5 cm and 20% for tumors < or = 1.5 cm. MIBI sensitivity was 90% (9/10) for lesions > or = 1.5 cm. Specificity was 93% for 201Tl and 83% for MIBI. There was no significant difference in 201Tl (1.76 +/- 0.55) and MIBI (1.82 +/- 0.95) tumor uptake ratios (p = 0.75). CONCLUSIONS Technetium-99m-MIBI was more sensitive than 201Tl for imaging lesions > or = 1.5 cm. Craniocaudal positioning minimized the camera-to-breast distance but did not increase 201Tl detection of tumors < 1.5 cm and increased background breast activity due to scatter.