Cardiac diffusion MRI based on stimulated-echo acquisition mode (STEAM) techniques is hampered by its inherent low signal-to-noise ratio (SNR) efficiency. Diffusion imaging using standard spin-echo (SE) techniques, on the other hand, offers higher SNRs but has been considered impractical for the beating heart due to excessive signal attenuation from cardiac bulk motion. In this work the effect of systolic cardiac motion on different diffusion-encoding schemes was studied in detail. Numerical simulations based on in vivo motion data (acquired by MRI tagging techniques) demonstrate an up to 10-fold decrease in bulk motion sensitivity of the diffusion encoding if the first-order moment of the diffusion-encoding gradients is nullified. It is shown that the remaining systolic phase pattern on the myocardium does not influence the magnitude images if the spatial resolution is chosen to be higher than 4 mm. Given these relatively low resolution requirements, we obtained in vivo diffusion-weighted (DW) short-axis images from four healthy volunteers using an SE-based diffusion-encoding sequence with excitation and refocusing in orthogonal planes for field of view (FOV) reduction. The results showed no significant signal loss due to cardiac motion, and the direction of the principal eigenvalues was found to be in good agreement with known myocardial fiber orientation. Magn Reson Med 57:331–337, 2007. © 2007 Wiley-Liss, Inc.