Full-field digital mammography (FFDM) has replaced screen-film mammography (SFM) in most breast screening programs. We analyzed the impact of this replacement on the screening outcome. The study population consisted of a consecutive series of 60 770 analog and 63 182 digital screens. During a 1-year follow-up, we collected breast imaging reports, biopsy results and surgical reports of all the referred women. The referral rate and the cancer detection rate at FFDM were, respectively, 3.0% and 6,6 parts per thousand, compared with 1.5% (P <0.001) and 4.9 parts per thousand (P <0.001) at SFM. Positive predictive values of referral and percutaneous biopsies were lower at FFDM, respectively, 21.9% versus 31.6% (P <0.001) and 42.9% versus 62.8% (P <0.001). Per 1000 screened women, there was a significant increase with FFDM versus SFM in the detection rate of low- and intermediate-grade ductal carcinoma in situ (DCIS) (+0.7), invasive T1a-c cancers (+0.9), invasive ductal cancers (+0.9), low-grade (+1.1), node-negative invasive cancers (+1.2), estrogen-receptor or progesterone-receptor-positive invasive cancers (respectively, +0.9 and +1.1) and Her2/Neu-negative (+0.8) invasive cancers. Mastectomy rates were stable at 1.1 per 1,000 screens. FFDM significantly increased the referral rate and cancer detection rate, at the expense of a lower positive predictive value of referral and biopsy. Extra tumors detected at FFDM were mostly low-intermediate grade DCIS and smaller invasive tumors, of more favorable tumor characteristics. Mastectomy rates were not increased in the FFDM population, while increased over-diagnosis cannot be excluded.