BACKGROUND. Contrast-enhanced mammography (CEM) is rapidly expanding as a credible alternative to MRI in various clinical settings. OBJECTIVE. The purpose of this study was to compare CEM and MRI for neoadjuvant therapy (NAT) response assessment in patients with breast cancer. METHODS. This prospective study included 51 patients (mean age, 46 ± 11 [SD] years) with biopsy-proven breast cancer who were candidates for NAT from May 2015 to April 2018. Patients underwent both CEM and MRI before, during, and after NAT (pre-NAT, mid-NAT, and post-NAT, respectively). Post-NAT CEM included a 6-minute delayed acquisition. One breast radiologist with experience in CEM reviewed CEM examinations; one breast radiologist with experience in MRI reviewed MRI examinations. The radiologists assessed for the presence of an enhancing lesion; if an enhancing lesion was detected, its size was measured. RECIST version 1.1 response assessment categories were derived. Pathologic complete response (pCR) was defined as absence of both invasive cancer and ductal carcinoma in situ (DCIS). RESULTS. Of 51 patients, 16 achieved pCR. CEM yielded systematically lower size measurements compared with MRI (mean difference, -0.2 mm for pre-NAT, -0.7 mm for mid-NAT, and -0.3 mm for post-NAT). All post-NAT imaging tests yielded systematically larger size measurements compared with pathology (mean difference, 0.8 mm for CEM, 1.2 mm for MRI, and 1.9 mm for delayed CEM). Of 12 patients with residual DCIS, an enhancing lesion was detected in seven on post-NAT CEM, eight on post-NAT MRI, and nine on post-NAT delayed CEM. Agreement of RECIST response categories between CEM and MRI, expressed as kappa coefficient, was 0.791 at mid-NAT and 0.871 at post-NAT. For detecting pCR by post-NAT imaging, sensitivity and specificity were 81% and 83% for CEM, 100% and 86% for MRI, and 81% and 89% for delayed CEM. Sensitivity was significantly higher for MRI than CEM (p = .001) and delayed CEM (p = .002); remaining comparisons were not significant (p > .05). CONCLUSION. After NAT for breast cancer, CEM and MRI yielded comparable assessments of lesion size (both slightly overestimated vs pathology) and RECIST categories and showed no significant difference in specificity for pCR. MRI had higher sensitivity for pCR. Delayed CEM acquisition may help detect residual DCIS. CLINICAL IMPACT. Although MRI remains the preferred test for NAT response monitoring, the findings support CEM as a useful alternative when MRI is contraindicated or not tolerated.