Background: In asymptomatic women at average risk, mammography alone, possibly amended by the US, is recommended for screening. MRI is established for screening women at high risk, but there are no data available to support its use in women at average risk. Methods: Between Jan 2005 and Dec 2012, 1,387 women at average risk, i.e. without personal or family history of breast or ovarian cancer or tissue diagnosis of atypias underwent 1,705 annual MRI screening studies. Mean/median age was 55/56, range 40-79. All women had normal CBE and normal double-read 2-view digital screening mammograms. In women with breast densities, additional US had been performed and women were included if also US was normal. Patients underwent bilateral DCE MRI at 1.5T using a 2D GE pulse sequence. Results: A total of 54 MRIs were rated positive (MR-BI-RADS 4/5) (54/1705; 3.2%). Biopsies performed in these women were positive for breast cancer or DCIS in 18, and revealed high risk lesions in 8 patients, yielding an additional cancer yield of 11/1,000. In 28 women, biopsy revealed benign changes only. This translates into a PPV of 33% (18/54), or 48% (26/54) if high risk lesions are included. Of the 18 cancers, 11 (61%) were invasive and 7 (39%) DCIS. Mean size of invasive cancers was 11 mm (median 10, range 4 -22). Invasive cancers were intermediate or high grade in 9/11, DCIS in 6/7. All invasive cancers were staged pN0, M0. Minimal cancer rate was 13/18 (72%). Distribution of mammographic breast densities in women with MRI-diagnosed cancer was as follows: ACR I in 2 (11%), ACR II in 3 (17%), ACR III in 8 (44%), ACR IV in 5 (28%). This was equivalent to the distribution of breast densities in the entire cohort. Conclusions: In this cohort of heavily pre-screened women at average risk, the additional cancer yield achieved through MRI was high (11/1,000). Although the biologic profile of MRI-only detected additional cancers was indicative of prognostically relevant disease, with a high proportion of high-grade cancers, stage distribution of cancers was favorable. Mammographic breast density did not predict the likelihood with which additional cancers were identified through MRI. In women with dense breasts who underwent screening US in addition to mammography, there is still a significant reservoir of undetected cancers.