AbstractPurposeTo investigate the effects of compartmental anisotropy on filtered exchange imaging (FEXI) in white matter (WM).Theory and MethodsFEXI signals were measured using multiple combinations of diffusion filter and detection directions in five healthy volunteers. Additional filters, including a trace‐weighted diffusion filter with trapezoidal gradients, a spherical b‐tensor encoded diffusion filter, and a T2 filter, were tested with trace‐weighted diffusion detection.ResultsA large range of apparent exchange rates (AXR) and both positive and negative filter efficiencies (σ) were found depending on the mutual orientation of the filter and detection gradients relative to WM fiber orientation. The data demonstrated that the fast‐diffusion compartment suppressed by diffusional filtering is not exclusively extra‐cellular, but also intra‐cellular. While not comprehensive, a simple two‐compartment diffusion tensor model with water exchange was able to account qualitatively for the trends in positive and negative filtering efficiencies, while standard model imaging (SMI) without exchange could not. This two‐compartment diffusion tensor model also demonstrated smaller AXR variances across subjects. When employing trace‐weighted diffusion detection, AXR values were on the order of the R₁ (=1/T1) of water at 3T for crossing fibers, while being less than R₁ for parallel fibers.ConclusionOrientation‐dependent AXR and σ values were observed when using multi‐orientation filter and detection gradients in FEXI, indicating that WM FEXI models need to account for compartmental anisotropy. When using trace‐weighted detection, AXR values were on the order of or less than R₁, complicating the interpretation of FEXI results in WM in terms of biological exchange properties. These findings may contribute toward better understanding of FEXI results in WM.