Background/Purpose <p>To evaluate the advantages of including versus excluding the tumor periphery and combining diffusion-weighted imaging (DWI) with T2-weighted imaging (T2w) for outcome predictions of preoperative radio(chemo)therapy in rectal cancer.</p> Methods <p>Four analysis strategies, based on two segmentation methods and two magnetic resonance imaging (MRI) sequences, were evaluated in 106 patients examined with pretreatment MRI. One segmentation method included the tumor periphery in the region of interest (ROI) encompassing the whole tumor (wROI), considered as the reference segmentation approach, and one included only the central part (cROI). Relevant radiomics imaging features were extracted from either T2w alone or from both T2w and DWI and used by a machine learning algorithm for the prediction of pathologic complete response (pCR), neoadjuvant rectal (NAR) score, and disease recurrence. The area under the curve (AUC) was the performance measure. AUCs were compared with a bootstrapping method based on 10⁴ bootstraps.</p> Results <p>cROI applied to both T2w and DWI provided the highest numerical prediction of pCR (AUC 0.76), however, not significantly superior to the other strategies (<i>p</i> ≥ 0.138). cROI applied to both T2w and DWI also yielded the highest numerical prediction of NAR score (AUC 0.84), showing advantages over wROI-based analysis strategies (AUC 0.66 and 0.69; <i>p</i> ≤ 0.008). When compared to cROI applied to T2w alone (AUC 0.73), the benefit was borderline statistically significant (p = <i>0.053</i>). For prediction of disease recurrence, no differences were found between the analysis strategies.</p> Conclusions <p>Inclusion of the tumor periphery in radiomic analysis of magnetic resonance images does not improve predictions of the preoperative therapy response in patients with rectal cancer. Excluding tumor periphery while adding DWI to T2w improves prediction of the NAR score, although it does not affect pCR or recurrence prediction.</p> Graphical abstract <p></p>