Purpose: To evaluate the added value of diffusion-weighted (DW) imaging in combination with T2-weighted magnetic resonance (MR) imaging compared with T2-weighted imaging alone for predicting tumor clearance of the mesorectal fascia (MRF) after neoadjuvant chemotherapy and radiation therapy (CRT) in patients with locally advanced rectal cancer. Materials and Methods: This retrospective study was approved by the institutional review board, and informed consent was waived. Forty-five patients with rectal cancer with clinically suspected MRF invasion who underwent neoadjuvant CRT and subsequent surgery were enrolled. All patients underwent pre- and post-CRT 3.0-T rectal MR imaging with DW imaging. Two observers independently reviewed a set of T2-weighted images and a combined set of T2-weighted and DW images and rated them by using a five-point scale. Diagnostic performance was evaluated for each observer with receiver operating characteristic (ROC) curve analysis. Accuracy, sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were assessed. The standard of reference was histopathologic findings in the surgical specimen. Pairwise comparison of the ROC curves was used to compare diagnostic performance between the two image sets; the McNemar test was used to compare accuracy, sensitivity, and specificity. Results: The diagnostic performance (area under the ROC curve [A(z)]) with respect to MRF tumor clearance of both observers improved significantly after additional review of DW images: A(z) improved from 0.770 to 0.918 (P = .017) for observer 1 and from 0.847 to 0.960 (P = .026) for observer 2. The diagnostic accuracy of DW combined with T2-weighted imaging (observer 1, 89% [40 of 45]; observer 2, 93% [42 of 45]), sensitivity (observer 1, 94% [31 of 33]; observer 2, 97% [32 of 33]) and NPV (observer 1, 82% [nine of 11]; observer 2, 91% [10 of 11]) were significantly higher than those of T2-weighted imaging alone (accuracy: observer 1, 40% [18 of 45], P < .001; observer 2, 69% [31 of 45], P = .022; sensitivity: observer 1, 21% [seven of 33], P < .001; observer 2, 67% [22 of 33], P = .002; NPV: observer 1, 30% [11 of 37], P = .013; observer 2, 45% [nine of 20], P = .025). Interobserver agreement of confidence levels was fair for T2-weighted imaging alone (κ = 0.212) but was excellent for the combined set of DW and T2-weighted images (κ = 0.880). Conclusion: Adding DW imaging to T2-weighted imaging can improve the prediction of tumor clearance in the MRF after neoadjuvant CRT compared with T2-weighted imaging alone in patients with locally advanced rectal cancer. © RSNA, 2011.