Background Full-field digital mammography (FFDM) has been accepted as a superior modality for breast cancer screening compared with conventional screen-film mammography (SFM), especially in women younger than 50 years or with dense breasts. Purpose To evaluate the accuracy of FFDM for breast cancer screening. Materials and Methods Data from January 1, 2011 to December 31, 2013 in the database from a nationwide breast cancer screening program linked with the national cancer registry were retrospectively analyzed. The study included Korean women aged 40-79 years who had undergone screening mammography with SFM, computed radiography (CR), or FFDM. The sensitivity, specificity, positive predictive value (PPV), and absolute and relative differences among these modalities were calculated, followed by pairwise comparison tests with multiple testing corrections. The areas under the receiver operating characteristic curve (AUCs) were also estimated and compared by using the DeLong method with Bonferroni correction. Results Among the 8 482 803 women included (mean age, 55 years ± 10), 34.4% (2 920 279 of 8 482 803), 51.7% (4 385 807 of 8 482 803), and 13.9% (1 176 717 of 8 482 803) underwent SFM, CR, and FFDM, respectively. The sensitivity and PPV were higher for FFDM than for SFM (adjusted odds ratio, 1.77 [95% confidence interval {CI}: 1.62, 1.95] for sensitivity and 1.36 [95% CI: 1.29, 1.43] for PPV) and CR (adjusted odds ratio, 1.70 [95% CI: 1.56, 1.85] for sensitivity and 1.26 [95% CI: 1.20, 1.32] for PPV), whereas specificity was lower with FFDM. The overall AUC for FFDM was 0.80 (95% CI: 0.80, 0.81), which was higher than that for SFM (0.75 [95% CI: 0.75, 0.76]) and CR (0.76 [95% CI: 0.75, 0.76]). P < .05 was found for differences in sensitivity, PPV, and AUC among modalities overall and in most of the subgroups of age, breast density, and screening round. Conclusion Full-field digital mammography allows better discrimination or prediction of breast cancer in the general female population than screen-film mammography or computed radiography, regardless of age, breast density, or screening round. © RSNA, 2019 Online supplemental material is available for this article.