PURPOSE: We aimed to compare the detection of breast cancer using full-field digital mammography (FFDM), FFDM with computer-aided detection (FFDM+CAD), ultrasound (US), and FFDM+CAD plus US (FFDM+CAD+US), and to investigate the factors affecting cancer detection. METHODS: In this retrospective study conducted from 2008 to 2012, 48,251 women underwent FFDM and US for cancer screening. One hundred seventy-one breast cancers were detected: 115 invasive cancers and 56 carcinomas in situ. Two radiologists evaluated the imaging findings of FFDM, FFDM+CAD, and US, based on the Breast Imaging Reporting and Data System lexicon of the American College of Radiology by consensus. We reviewed the clinical and the pathological data to investigate factors affecting cancer detection. We statistically used generalized estimation equations with a logit link to compare the cancer detectability of different imaging modalities. To compare the various factors affecting detection versus nondetection, we used Wilcoxon rank sum, chi-square, or Fisher exact test. RESULTS: The detectability of breast cancer by US (96.5%) or FFDM+CAD+US (100%) was superior to that of FFDM (87.1%) (p=0.019 or p<0.001, respectively) or FFDM+ CAD (88.3%) (p=0.050 or p<0.001, respectively). However, cancer detectability was not significantly different between FFDM versus FFDM+CAD (p=1.000) and US alone versus FFDM+CAD+US (p=0.126). The tumor size influenced cancer detectability by all imaging modalities (p<0.050). In FFDM and FFDM+CAD, the nondetecting group consisted of younger patients and patients with a denser breast composition (p<0.050). In breast US, carcinoma in situ was more frequent in the nondetecting group (p=0.014). CONCLUSION: For breast cancer screening, breast US alone is satisfactory for all age groups, although FFDM+ CAD+US is the perfect screening method. Patient age, breast composition, and pathological tumor size and type may influence cancer detection during screening.