Objective: To compare the diagnostic performance of contrast-enhanced spectral mammography (CESM) versus ultrasonography (US) in symptomatic patients with dense breasts, while using histology as the gold standard. Materials and Methods: After obtaining approval from the local ethics board, this prospective study collected data from patients with symptomatic breasts who underwent CESM and US examinations from May 1, 2017 to September 30, 2017. We then selected those with dense breasts and pathological results as our sample population. Both CESM and US results were classified by a radiologist through the Breast Imaging Reporting and Data System, and the results were compared with their corresponding histological results. The chi-square test was conducted to compare the diagnostic performance of CESM and US, and the receiver operating characteristic curves for the two imaging modalities were obtained. Results: A total of 131 lesions from 115 patients with dense breasts were included in this study. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 93.8%, 88.1%, 88.2%, 93.7%, and 90.8% for CESM, and 90.6%, 82.1%, 82.9%, 90.2%, and 86.3% for US, respectively. The p values for sensitivity, specificity, PPV, NPV, and accuracy were 0.687, 0.388, 0.370, 0.702, and 0.238, respectively. The area under the curve of CESM (0.917) was comparable with that of US (0.884); however, the differences between CESM and US were not statistically significant (p = 0.225). Eight false-positive cases and 4 false-negative cases for breast cancer were found in CESM, while 12 false-positive cases and 6 false-negative cases were found in US. Conclusion: The diagnostic performances of CESM and US are comparable in symptomatic women with dense breasts; however, the routine use of additional US imaging is questionable for lesions that can be detected by CESM.