Background <p>The purpose of this study was to compare the perioperative efficacy and safety of neoadjuvant chemoradiotherapy (NCRT) alone versus short-course radiotherapy combined with immunochemotherapy (SCRT + ICT) in patients with proficient mismatch repair (pMMR) rectal cancer.</p> Methods <p>This study was designed as a single-center, retrospective, case-matched analysis conducted at a tertiary referral center. The patient cohort consisted of individuals diagnosed with pMMR rectal cancer between 2022 and 2024. The main outcome measures evaluated were pathological complete response (pCR) rate, anus preservation rate, neoadjuvant therapy-related adverse events, and surgery-related complications.</p> Results <p>In the final analysis, 46 pairs of patients were included. The SCRT + ICT group had a significantly higher pathological complete response (pCR) rate (47.8% versus 10.9%, <i>P</i> &lt; 0.001) and anus preservation rate (84.8% versus 37.0%, <i>P</i> &lt; 0.001), but also a higher temporary stoma rate (76.1% versus 21.7%, <i>P</i> &lt; 0.001). Both groups achieved a 100% R0 resection rate. Regarding safety, the combined therapy group had lower intraoperative blood loss (20&#xa0;ml versus 50&#xa0;ml, <i>P</i> &lt; 0.001) and shorter postoperative hospital stay (6&#xa0;days versus 8&#xa0;days, <i>P</i> &lt; 0.001). Adverse events and postoperative complications were similar in both groups. Additionally, logistic regression analysis showed that SCRT + ICT is a protective factor for achieving postoperative pCR, while intraoperative blood loss ≥ 50&#xa0;ml and elevated pretreatment carcinoembryonic antigen (CEA) levels are risk factors for postoperative pCR.</p> Conclusions <p>Short-course radiotherapy combined with immunochemotherapy is safe and effective for patients with pMMR rectal cancer.</p>