Purpose: To design a preparation module for vessel signal suppression in MR neurography of the extremities, which causes minimal attenuation of nerve signal and is highly insensitive to eddy currents and motion. Methods: The orthogonally combined motion-and diffusionsensitized driven equilibrium (OC-MDSDE) preparation was proposed, based on the improved motion-and diffusionsensitized driven equilibrium methods (iMSDE and FC-DSDE, respectively), with specific gradient design and orientation. OC-MDSDE was desensitized against eddy currents using appropriately designed gradient prepulses. The motion sensitivity and vessel signal suppression capability of OC-MDSDE and its components were assessed in vivo in the knee using 3D turbo spin echo (TSE). Nerve-to-vessel signal ratios were measured for iMSDE and OC-MDSDE in 7 subjects. Results: iMSDE was shown to be highly sensitive to motion with increasing flow sensitization. FC-DSDE showed robustness against motion, but resulted in strong nerve signal loss with diffusion gradients oriented parallel to the nerve. OC-MDSDE showed superior vessel suppression compared to iMSDE and FC-DSDE and maintained high nerve signal. Mean nerve-to-vessel signal ratios in 7 subjects were 0.40 6 0.17 for iMSDE and 0.63 6 0.37 for OC-MDSDE. Conclusion: OC-MDSDE combined with 3D TSE in the extremities allows high-near-isotropic-resolution imaging of peripheral nerves with reduced vessel contamination and high nerve signal. Magn Reson Med 79:407-415, 2018. V C 2017 Wiley Periodicals, Inc.