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Abstract Geostatistical modeling for continuous point‐referenced data has extensively been applied to neuroimaging because it produces efficient and valid statistical inference. However, diffusion tensor imaging (DTI), a neuroimaging technique characterizing the brain's anatomical structure, produces a positive‐definite (p.d.) matrix for each voxel. Currently, only a few geostatistical models for p.d. matrices have been proposed because introducing spatial dependence among p.d. matrices properly is challenging. In this paper, we use the spatial Wishart process, a spatial stochastic process (random field), where each p.d. matrix‐variate random variable marginally follows a Wishart distribution, and spatial dependence between random matrices is induced by latent Gaussian processes. This process is valid on an uncountable collection of spatial locations and is almost‐surely continuous, leading to a reasonable way of modeling spatial dependence. Motivated by a DTI data set of cocaine users, we propose a spatial matrix‐variate regression model based on the spatial Wishart process. A problematic issue is that the spatial Wishart process has no closed‐form density function. Hence, we propose an approximation method to obtain a feasible Cholesky decomposition model, which we show to be asymptotically equivalent to the spatial Wishart process model. A local likelihood approximation method is also applied to achieve fast computation. The simulation studies and real data application demonstrate that the Cholesky decomposition process model produces reliable inference and improved performance, compared to other methods.