OBJECTIVE The aim of this study was to analyze the role of non-echo-planar imaging (non-EPI)-based diffusion-weighted (DW) magnetic resonance imaging (MRI) for the detection of residual cholesteatoma after canal wall-up mastoidectomy before eventual second-look surgery. METHODS Prospective and blinded study. METHODS Tertiary referral center. METHODS The study group included the surgical, clinical, and imaging follow-up of 32 consecutive patients after primary cholesteatoma surgery. METHODS All patients were investigated with MRI, including late postgadolinium T1-weighted sequence and non-EPI-DW sequence, 10 to 18 months after first-stage cholesteatoma surgery by experienced surgeons using a canal wall-up mastoidectomy. The non-EPI-DW images were evaluated for the presence of a high-signal intensity lesion consistent with residual cholesteatoma. Imaging findings were correlated with findings from second-stage surgery in 19 patients, clinical follow-up examination in 11 patients, and, in 2 patients, clinical and MRI follow-up examination. RESULTS Non-EPI-DW sequences depicted 9 of 10 residual cholesteatomas. The only lesion missed was a 2-mm cholesteatoma in an examination degraded by motion artifacts in a child. All other diagnosed cholesteatomas measured between 2 and 6 mm. Sensitivity, specificity, positive predictive value, and negative predictive value were 90, 100, 100, and 96%, respectively. CONCLUSIONS Except for motion artifact-degraded examinations, non-EPI-DW MRI is able to detect even very small residual cholesteatoma after first-stage surgery by showing a high-signal intensity lesion. It has the capability of selecting patients for second-look surgery, avoiding unnecessary second-look surgery.