Background Contrast-enhanced mammography (CEM) is a more accessible alternative to contrast-enhanced MRI (CE-MRI) in breast imaging, but a summary comparison of published studies is lacking. Purpose To directly compare the performance of CEM and CE-MRI regarding sensitivity, specificity, and negative predictive value in detecting breast cancer, involving all publicly available studies in the English language. Materials and Methods Two readers extracted characteristics of studies investigating the comparative diagnostic performance of CEM and CE-MRI in detecting breast cancer. Studies published until April 2021 were eligible. Sensitivity, specificity, negative predictive value, and positive and negative likelihood ratios were calculated using bivariate random effects models. A Fagan nomogram was used to identify the maximum pretest probability at which posttest probabilities of a negative CEM or CE-MRI examination were in line with the 2% malignancy rate benchmark for downgrading a Breast Imaging Reporting and Data System (BI-RADS) category 4 to a BI-RADS category 3 result. I 2 statistics, Deeks funnel plot asymmetry test for publication bias, and meta-regression were used. Results Seven studies investigating 1137 lesions (654 malignant, 483 benign) with an average cancer prevalence of 65.3% (range: 47.3%-82.2%) were included. No publication bias was found (P = .57). While the positive likelihood ratio was equal at a value of 3.1 for CE-MRI and 3.6 for CEM, the negative likelihood ratio of CE-MRI (0.04) was lower than that with CEM (0.12). CE-MRI had higher sensitivity for breast cancer than CEM (97% [95% CI: 86, 99] vs 91% [95% CI: 77, 97], respectively; P < .001) but lower specificity (69% [95% CI: 46, 85] vs 74% [95% CI: 52, 89]; P = .09). A Fagan nomogram demonstrated that the maximum pretest probability at which both tests could rule out breast cancer was 33% for CE-MRI and 14% for CEM. Furthermore, iodine concentration was positively associated with CEM sensitivity and negatively associated with its specificity (P = .04 and P < .001, respectively). Conclusion Contrast-enhanced MRI had superior sensitivity and negative likelihood ratios with higher pretest probabilities to rule out malignancy compared with contrast-enhanced mammography. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Mann and Veldhuis in this issue.