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Objectives. To evaluate the potential of contrast-enhanced spectral mammography (CESM) in reducing benign breast biopsy rate, thereby improving resource utilization. To explore its potential as a value-adding modality in the management of BI-RADS 4/5 lesions. Materials and Methods. This was a prospective study conducted between July 2016 and September 2018. Patients with BI-RADS 4/5 lesions detected on conventional imaging (mammogram, digital breast tomosynthesis, and ultrasound) were enrolled for adjunct CESM. Histopathologic correlation was done for all lesions. Additional suspicious lesions detected on CESM were all identified on second-look ultrasound and subsequently biopsied. Images were evaluated independently by two radiologists trained in breast imaging using BI-RADS classification. Presence of enhancement on CESM, BI-RADS score, and histopathology of each lesion were analyzed and tested with the chi-square/fisher-exact test for statistical significance. Results. The study included 105 lesions in 63 participants—1 man and 62 women, an average age of 53.7 ± 10.8 years. On CESM, 22 (20.9%) of the lesions did not show enhancement. All 22 lesions had been classified as BI-RADS 4A and were subsequently proven to be benign. Of the remaining 83 enhancing lesions, 54 (65.1%) were malignant and 29 (34.9%) were benign ( p < 0.05 ). CESM detected 6 additional lesions which were not identified on initial conventional imaging. Four of these were proven malignant and were in a different quadrant than the primary lesion investigated. Conclusion. There is evidence that the absence of enhancement in CESM strongly favors benignity. It may provide the reporting radiologist with greater confidence in imaging assessment, especially in BI-RADS 4A cases, where a proportion of them are in actuality BI-RADS 3. Greater accuracy of BI-RADS grading can reduce nearly half of benign biopsies and allow better resource allocation. CESM also increases the detection rate of potentially malignant lesions, thereby changing the treatment strategies.