Purpose To investigate the performance of integrated approaches that combined intravoxel incoherent motion (IVIM) and non-Gaussian diffusion parameters compared with the Breast Imaging and Reporting Data System (BI-RADS) to establish multiparameter thresholds scores or probabilities by using Bayesian analysis to distinguish malignant from benign breast lesions and their correlation with molecular prognostic factors. Materials and Methods Between May 2013 and March 2015, 411 patients were prospectively enrolled and 199 patients (allocated to training [n = 99] and validation [n = 100] sets) were included in this study. IVIM parameters (flowing blood volume fraction [fIVIM] and pseudodiffusion coefficient [D*]) and non-Gaussian diffusion parameters (theoretical apparent diffusion coefficient [ADC] at b value of 0 sec/mm2 [ADC0] and kurtosis [K]) by using IVIM and kurtosis models were estimated from diffusion-weighted image series (16 b values up to 2500 sec/mm2), as well as a synthetic ADC (sADC) calculated by using b values of 200 and 1500 (sADC200-1500) and a standard ADC calculated by using b values of 0 and 800 sec/mm2 (ADC0-800). The performance of two diagnostic approaches (combined parameter thresholds and Bayesian analysis) combining IVIM and diffusion parameters was evaluated and compared with BI-RADS performance. The Mann-Whitney U test and a nonparametric multiple comparison test were used to compare their performance to determine benignity or malignancy and as molecular prognostic biomarkers and subtypes of breast cancer. Results Significant differences were found between malignant and benign breast lesions for IVIM and non-Gaussian diffusion parameters (ADC0, K, fIVIM, fIVIM · D*, sADC200-1500, and ADC0-800; P < .05). Sensitivity and specificity for the validation set by radiologists A and B were as follows: sensitivity, 94.7% and 89.5%, and specificity, 75.0% and 79.2% for sADC200-1500, respectively; sensitivity, 94.7% and 96.1%, and specificity, 75.0% and 66.7%, for the combined thresholds approach, respectively; sensitivity, 92.1% and 92.1%, and specificity, 83.3% and 66.7%, for Bayesian analysis, respectively; and sensitivity and specificity, 100% and 79.2%, for BI-RADS, respectively. The significant difference in values of sADC200-1500 in progesterone receptor status (P = .002) was noted. sADC200-1500 was significantly different between histologic subtypes (P = .006). Conclusion Approaches that combined various IVIM and non-Gaussian diffusion MR imaging parameters may provide BI-RADS-equivalent scores almost comparable to BI-RADS categories without the use of contrast agents. Non-Gaussian diffusion parameters also differed by biologic prognostic factors. © RSNA, 2017 Online supplemental material is available for this article.