Background: To create a predictive score of malignancy of a breast lesion based on the main contrast enhancement features ascertained by contrast-enhanced spectral mammography (CESM). Methods: In this single-centre prospective study, patients with suspicious breast lesions (BIRADS > 3) were enrolled between January 2013 and February 2022. All participants underwent CESM prior to breast biopsy, and eventually surgery. A radiologist with 20 years’ experience in breast imaging evaluated the presence or absence of enhancement and the following enhancement descriptors: intensity, pattern, margin, and ground glass. A score of 0 or 1 was given for each descriptor, depending on whether the enhancement characteristic was predictive of benignity or malignancy (both in situ and invasive). Then, an overall enhancement score ranging from 0 to 4 was obtained. The histological results were considered the gold standard in the evaluation of the relationship between enhancement patterns and malignancy. Results: A total of 321 women (median age: 51 years; range: 22–83) with 377 suspicious breast lesions were evaluated. Two hundred forty-nine lesions (66%) have malignant histological results (217 invasive and 32 in situ). Considering an overall enhancement score ≥ 2 as predictive of malignancy, we obtain an overall sensitivity of 92.4%; specificity of 89.8%; positive predictive value of 94.7%; and negative predictive value of 85.8%. Conclusions: Our proposed predictive score on the enhancement descriptors of CESM to predict the malignancy of a breast lesion shows excellent results and can help in early breast cancer diagnosis and in avoiding unnecessary biopsies.