The purpose of this study was to evaluate the feasibility of a centric-reordered modified rapid acquisition with relaxation enhancement (mRARE) sequence for single-shot diffusion-weighted magnetic resonance imaging (DWI) of soft-tissue tumors in the musculoskeletal system. In the evaluation of this sequence, DWI was performed in a liquid phantom, in excised human tumor samples embedded in bovine muscle, and in nine patients suffering from different types of soft-tissue tumors. The measurements were compared to DWI using a spin-echo sequence and a single-shot echo planar imaging (EPI) sequence. The phantom measurements in water and dimethyl sulfoxide showed a difference of less than 5% when comparing the apparent diffusion coefficients (ADCs) determined by the mRARE sequence and the two other techniques. Comparing mRARE and EPI, the differences in the ADCs were about 10% in the excised tumor tissue and, typically, about 15% in vivo. ADCs between 0.8 x 10(-3) mm2/s and 1.4 x 10(-3) mm2/s, depending on the tumor type, were found in solid tumor tissue; in cystic tumor areas, ADCs greater than 2.0 x 10(-3) mm2/s were determined with the mRARE and the EPI sequences. Diffusion-weighted images of the mRARE sequence were less distorted than those acquired with the single-shot EPI sequence, and provided more anatomic information, since the muscle and fat signals were considerably higher.