Early detection of the response of hepatocellular carcinoma (HCC) to yttrium-90 radioembolization therapy may be important to permit repeat radioembolization or alternative treatment options. Water-mobility measurements with use of diffusion-weighted (DW) magnetic resonance (MR) imaging are useful for noninvasive interrogation of microstructural tissue properties. Findings of DW MR imaging may serve as an early biomarker of HCC response. This study tested the hypothesis that DW MR imaging can detect changes in tumor tissue water diffusion in response to (90)Y therapy. In each of six patients with HCC included in the study, tumor water diffusion increased significantly after therapy. DW MR imaging is a promising technique for noninvasive assessment of tumor response to (90)Y radioembolization.