Background <p>Neoadjuvant combination immunotherapy is a potential treatment option for patients with proficient mismatch repair/microsatellite stable colorectal cancer. Preoperative screening via endoscopy and imaging examinations could help identify patients who may potentially achieve a complete response after neoadjuvant combination immunotherapy. This study aims to evaluate the diagnostic accuracy of endoscopic and imaging examinations in predicting pathological complete response after neoadjuvant combination immunotherapy.</p> Methods <p>This single-center, retrospective, observational study included patients diagnosed with colorectal cancer by biopsy between 2015 and 2023 at a tertiary referral center. The main outcome measures included endoscopic examination, imaging findings, and pathological results after neoadjuvant combination immunotherapy.</p> Results <p>This study included 36 patients with locally advanced proficient mismatch repair colorectal cancer. Postoperative pathology revealed that 17 patients (47.2%) achieved a complete response (ypT0N0). The sensitivity, specificity, and accuracy of the endoscopic ypT0N0 diagnosis were 62.5%, 80.0%, and 80.6%, respectively; those of imaging-based ypT0N0 diagnosis were 43.8%, 100%, and 75.0%, respectively; and those of the combined diagnosis were 37.5%, 100%, and 72.2%, respectively. The areas under the receiver-operating characteristic curve for the endoscopic and imaging ypT0N0 diagnoses were 0.768 and 0.706, respectively.</p> Conclusions <p>The specificities of endoscopy and imaging for diagnosing complete response after neoadjuvant combination immunotherapy for colorectal cancer were high; however, sensitivities were low. Therefore, radical surgery should still be recommended for patients with an incomplete response based on either examination. Larger scale studies are required to determine if a watch-and-wait strategy is suitable for patients with a complete response based on these two examinations.</p>