Background: Without the need of contrast media, diffusion-weighted imaging (DWI) has shown great promise for accurate detection of lipid-rich necrotic core (LRNC), a well-known feature of vulnerable plaques. However, limited resolution and poor image quality in vivo with conventional single-shot diffusion-weighted echo planar imaging (SS-DWEPI) has hindered its clinical application. The aim of this work is to develop a diffusion-prepared turbo-spin-echo (DP-TSE) technique for carotid plaque characterization with 3D high resolution and improved image quality. Methods: Unlike SS-DWEPI where the diffusion encoding is integrated in the EPI framework, DP-TSE uses a diffusion encoding module separated from the TSE framework, allowing for segmented acquisition without the sensitivity to phase errors. The interleaved, motion-compensated sequence was designed to enable 3D black-blood DWI of carotid arteries with sub-millimeter resolution. The sequence was tested on 12 healthy subjects and compared with SS-DWEPI for image quality, vessel wall visibility, and vessel wall thickness measurements. A pilot study was performed on 6 patients with carotid plaques using this sequence and compared with conventional contrast-enhanced multi-contrast 2D TSE as the reference. Results: DP-TSE demonstrated advantages over SS-DWEPI for resolution and image quality. In the healthy subjects, vessel wall visibility was significantly higher with diffusion-prepared TSE (p < 0.001). Vessel wall thicknesses measured from diffusion-prepared TSE were on average 35% thinner than those from the EPI images due to less distortion and partial volume effect (p < 0.001). ADC measurements of healthy carotid vessel wall are 1.53 +/- 0.23 x 10(-3) mm(2)/s. In patients the mean ADC measurements in the LRNC area were significantly lower (0.60 +/- 0.16 x 10(-3) mm(2)/s) than those of the fibrous plaque tissue (1.27 +/- 0.29 x 10(-3) mm(2)/s, p < 0.01). Conclusions: Diffusion-prepared CMR allows, for the first time, 3D DWI of the carotid arterial wall in vivo with high spatial resolution and improved image quality over SS-DWEPI. It can potentially detect LRNC without the use of contrast agents, allowing plaque characterization in patients with renal insufficiency.