PurposeThe analysis of diffusion data obtained under large gradient nonlinearities necessitates corrections during data reconstruction and analysis. While two such preprocessing pipelines have been proposed, no comparative studies assessing their performance exist. Furthermore, both pipelines neglect the impact of subject motion during acquisition, which, in the presence of gradient nonlinearities, induces spatio‐temporal B‐matrix variations. Here, spatio‐temporal B‐matrix tracking (STB) is proposed and its performance compared to established pipelines.MethodsDiffusion tensor MRI (DT‐MRI) was performed using a 300 mT/m gradient system. Data were acquired with volunteers positioned in regions with pronounced gradient nonlinearities, and used to compare the performance of six different processing pipelines, including STB.ResultsUp to 30% errors were observed in DT‐MRI parameter estimates when neglecting gradient nonlinearities. Moreover, the order in which inhomogeneity, eddy current and gradient nonlinearity corrections were performed was found to impact the consistency of parameter estimates significantly. Although, no pipeline emerged as a clear winner, the STB approach seemed to yield the most consistent parameter estimates under large gradient nonlinearities.ConclusionsUnder large gradient nonlinearities, the choice of preprocessing pipeline significantly impacts the estimated diffusion parameters. Motion‐induced spatio‐temporal B‐matrix variations can lead to systematic bias in the parameter estimates, that can be ameliorated using the proposed STB framework.