PURPOSE To investigate the respective diagnostic accuracies of the different breast imaging modalities, i. e., mammography (Mx), high-frequency breast ultrasound (US), and dynamic contrast-enhanced breast (MRI) regarding the early diagnosis of familial (hereditary) breast cancer. MATERIALS AND METHODS A prospective, non-randomized controlled clinical multi-center trial is performed at 4 academic tertiary care centers in Germany (Ulm, Munchen/Grosshadern, Munster and Bonn) for a total period of 4 years, sponsored by the German Cancer Aid. The protocol consists of semiannual clinical visits and breast ultrasound, and annual bilateral two-view Mx, US and MRI. Imaging studies were first analyzed independently, then Mx was read in conjunction with US, followed by Mx combined with MRI, and finally, all three imaging modalities were read in synopsis. We present the concept and first results of this trial. RESULTS So far, 748 screening rounds are available for analysis in 613 women. A total of 12 breast cancers have been identified, with 11/12 cases in the pTis or pT1/N0 stage. The mean size of detected invasive cancers was 7 mm. A total of 19 benign lesions were biopsied due to false-positive imaging diagnoses. The breast cancer detection rates were: Mx: 5/12 (42 %), US 3/12 (25 %), MRI 10/12 (83 %), and the positive predictive values: Mx 5/17 (29 %), US 3/15 (30 %), and MRI 10/23 (43 %). CONCLUSION The preliminary data suggest that early diagnosis of familial breast cancer is feasible by intensified surveillance, in particular with the addition of MRI.