BACKGROUND AND PURPOSE: To prospectively evaluate the signal-to-noise ratio (SNR) improvement in diffusion-weighted imaging (DWI) of the spine with the use of a newly developed non-Carr-Purcell-Meiboom-Gill (non-CPMG) single-shot fast spin-echo (SS-FSE) sequence and its effect on apparent diffusion coefficient (ADC) measurements. MATERIALS AND METHODS: Twenty-four patients were enrolled after written informed consent. DWI of the spine was obtained with an echo-planar imaging (EPI)-based sequence followed by a non-CPMG SS-FSE technique. SNR and ADC values were measured over a lesion-free vertebral corpus. A quality score was assigned for each set of images to assess the image quality. When a spinal lesion was present, contrast-to-noise ratio (CNR) and ADC were also measured. Student t tests were used for statistical analysis. RESULTS: Mean SNR values were 5.83 ± 2.2 and 11.68 ± 2.87 for EPI and non-CPMG SS-FSE DWI, respectively. SNR values measured in DWI using parallel imaging were found to be significantly higher (P < .01). Mean ADCs of the spine were 0.53 ± 0.15 and 0.35 ± 0.15 × 10-3 mm2/s for EPI and non-CPMG SS-FSE DWI, respectively. Quality scores were found to be higher for the non-CPMG SS-FSE DWI technique (P < .05). Overall lesion CNR was found to be higher in DWI with non-CPMG SS-FSE. CONCLUSION: The non-CPMG SS-FSE technique provides a significant improvement to current EPI-based DWI of the spine. A study including a larger number of patients is required to determine the use of this DWI sequence as a supplementary tool to conventional MR imaging for increasing diagnostic confidence in spinal pathologic conditions.