BACKGROUND AND PURPOSE: Imaging-based tumor grading is highly desirable but faces challenges in sensitivity, specificity, and diagnostic accuracy. A recently proposed diffusion imaging method by using a fractional order calculus model offers a set of new parameters to probe not only the diffusion process itself but also intravoxel tissue structures, providing new opportunities for noninvasive tumor grading. This study aimed to demonstrate the feasibility of using the fractional order calculus model to differentiate low- from high-grade gliomas in adult patients and illustrate its improved performance over a conventional diffusion imaging method using ADC (or D). MATERIALS AND METHODS: Fifty-four adult patients (18-70 years of age) with histology-proved gliomas were enrolled and divided into low-grade (n = 24) and high-grade (n = 30) groups. Multi-b-value diffusion MR imaging was performed with 17 b-values (0-4000 s/mm(2)) and was analyzed by using a fractional order calculus model. Mean values and SDs of 3 fractional order calculus parameters (D, beta, and mu) were calculated from the normal contralateral thalamus (as a control) and the tumors, respectively. On the basis of these values, the low and high-grade glioma groups were compared by using a Mann-Whitney U test. Receiver operating characteristic analysis was performed to assess the performance of individual parameters and the combination of multiple parameters for low- versus high-grade differentiation. RESULTS: Each of the 3 fractional order calculus parameters exhibited a statistically higher value (P <= .011) in the low-grade than in the high-grade gliomas, whereas there was no difference in the normal contralateral thalamus (P >= .706). The receiver operating characteristic analysis showed that beta (area under the curve = 0.853) produced a higher area under the curve than D (0.781) or mu (0.703) and offered a sensitivity of 87.5%, specificity of 76.7%, and diagnostic accuracy of 82.1%. CONCLUSIONS: The study demonstrated the feasibility of using a non-Gaussian fractional order calculus diffusion model to differentiate low- and high-grade gliomas. While all 3 fractional order calculus parameters showed statistically significant differences between the 2 groups, (3 exhibited a better performance than the other 2 parameters, including ADC (or D).