To prospectively evaluate ultrasonographic (US) lesion detection and characterization in a breast phantom by potential investigators in a screening US protocol, American College of Radiology Imaging Network (ACRIN) 6666. National Cancer Institute Cancer Experimental Therapeutic Protocol review and ACRIN internal institutional review board approved the protocol; potential investigators were informed of the study purpose prior to participation. Six equivalent anthropomorphic phantoms were prepared with 17 masses (2-10 mm in mean diameter) in different locations at different depths. Sixty-six investigators, experienced in breast US, from 23 institutions scanned a phantom with high-frequency linear-array transducers (12-5 MHz). Lesion location, diameters, echogenicity, shape, and posterior features were recorded. Reader-specific phantom maps were generated and compared with known lesion locations and features. Results from 64 observers could be analyzed and were masked to investigator identity. Agreement on US features was measured with kappa statistics. A generalized linear model generated log relative risks for detection rates as a function of lesion diameter, depth, and features. Of 17 lesions, a median of 14 (82%) were detected (range, 9-16), and 86% of observers detected at least 12 lesions. Of 1088 potential detections, 861 (79.1%) were made. Among 5-10-mm lesions, 499 (97.5%) of 512 detections were made (excluding a 6-mm "skin" lesion seen by only seven observers [11%]). One 4-mm mass was seen by 53 observers (83%). Among 3-mm lesions, 274 (71.4%) of 384 detections were made. One 2-mm lesion was seen by 28 (44%) observers. Relative risk of detection decreased to 0.55 (95% confidence interval: 0.51, 0.59) for each centimeter increase in lesion depth. Agreement was slight for lesion shape (kappa=0.14), substantial for echogenicity (kappa=0.61), and moderate for posterior features (kappa=0.45). Feature description errors were common for 2-4-mm lesions; only 33% of 3-mm anechoic masses were so characterized. Among eight 6-10-mm lesions, investigators erred in feature description of a median of 1 lesion (mean, 1.3; range, 0-4). US detection and description of lesions in a breast phantom were highly consistent for lesions 5-10 mm in diameter; those smaller than 5 mm were less reliably identified or characterized by experienced investigators.