Background: In our previous study, we developed a combined diagnostic model based on time-intensity curve (TIC) types and radiomics signature on contrast-enhanced magnetic resonance imaging (CE-MRI) for non-mass enhancement (NME). The model had a high diagnostic ability for differentiation without the additional diffusion-weighted imaging (DWI) sequence. In this study, we aimed to compare the diagnostic performance of the combined clinical-radiomics model based on CE-MRI and DWI in discriminating Breast Imaging-Reporting and Data System (BI-RADS) 4 NME breast lesions, ductal carcinoma in situ (DCIS), and invasive carcinoma.Methods: This retrospective study enrolled 364 NME lesions (343 patients). Of these, 183 malignant and 84 benign breast lesions classified as BI-RADS 4 NMEs by the initial diagnosis were reclassified based on the combined clinical-radiomics model and DWI, respectively. The nomogram score (NS) values for malignancy risk derived from the combined clinical-radiomics model and the minimal apparent diffusion coefficient (ADC) values from DWI were calculated and compared. The percentage of false positives were estimated in comparison with the original classification. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic value of the NS and minimal ADC values in distinguishing benign and malignant lesions, DCIS, and invasive breast carcinoma. An ablation experiment was used to test the value of the additional DWI sequence.Results: The diagnostic value of the NS values [area under curve (AUC) =0.843; 95% CI: 0.789-0.896] for discriminating the 267 NME breast lesions categorized as BI-RADS 4 was significantly higher than the minimal ADC values (AUC =0.662; 95% CI: 0.590-0.735). The NS values showed higher sensitivity, specificity, and accuracy compared with the minimal ADC values (sensitivity: 80.3% vs. 65.6%; specificity: 79.8% vs. 65.5%; accuracy: 80.1% vs. 65.5%). The NS values and minimal ADC values did not achieve high diagnostic accuracy in discriminating between DCIS and invasive cancer. However, the diagnostic performance of the combined NS-ADC model (AUC =0.731; 95% CI: 0.655-0.806) was higher than that ofConclusions: The combined clinical-radiomics model based on CE-MRI could improve the diagnostic performance in discriminating the BI-RADS 4 NME lesions without an additional DWI sequence. However, DWI may improve the diagnostic performance in discriminating DCIS from invasive cancer.