Diffusion kurtosis imaging (DKI) is used to differentiate between benign and malignant breast lesions. DKI fits are performed either on voxel-by-voxel basis or using volume-averaged signal. Investigate and compare DKI parameters' diagnostic performance using voxel-by-voxel and volume-averaged signal fit approach. Retrospective. A total of 104 patients, aged 24.1-86.4 years. A 3 T Spin-echo planar diffusion-weighted sequence with b-values: 50 s/mm2 , 750 s/mm2 , and 1500 s/mm2 . Dynamic contrast enhanced (DCE) sequence. Lesions were manually segmented by M.P. under supervision of S.O. (2 and 5 years of experience in breast MRI). DKI fits were performed on voxel-by-voxel basis and with volume-averaged signal. Diagnostic performance of DKI parameters (kurtosis corrected diffusion coefficient) and kurtosis was compared between both approaches. Receiver operating characteristics analysis and area under the curve (AUC) values were computed. Wilcoxon rank sum and Students t-test tested DKI parameters for significant (P <0.05) difference between benign and malignant lesions. DeLong test was used to test the DKI parameter performance for significant fit approach dependency. Correlation between parameters of the two approaches was determined by Pearson correlation coefficient. DKI parameters were significantly different between benign and malignant lesions for both fit approaches. Median benign vs. malignant values for voxel-by-voxel and volume-averaged approach were 2.00 vs. 1.28 ( in μm2 /msec), 2.03 vs. 1.26 ( in μm2 /msec), 0.54 vs. 0.90 ( ), 0.55 vs. 0.99 ( ). AUC for voxel-by-voxel and volume-averaged fit were 0.9494 and 0.9508 ( ); 0.9175 and 0.9298 ( ). For both, AUC did not differ significantly (P=0.20). Correlation of values between the two approaches was very high (r=0.99 for and r=0.97 for ). Voxel-by-voxel and volume-averaged signal fit approach are equally well suited for differentiating between benign and malignant breast lesions in DKI. 3 TECHNICAL EFFICACY: Stage 3.