Purpose Immunotherapy is emerging as a revolutionary treatment for mismatch repair deficient (dMMR) colorectal adenocarcinoma in both the metastatic and localised setting. Our multidisciplinary team noted that despite some patients demonstrating an excellent tumour response, they subsequently developed large bowel obstruction at the site of the primary tumour requiring surgical or endoscopic intervention. Methodology Data on all patients with dMMR colorectal cancer commenced on pembrolizumab following discussion at our multidisciplinary gastrointestinal cancer meeting was retrospectively reviewed and cases who developed large bowel obstruction identified. A detailed case review of the patient’s notes, imaging and pathology was performed. Informed consent was obtained from each patient. Results Three patients (2:1 F/M) with metastatic and locally advanced dMMR colorectal cancer treated with pembrolizumab developed large bowel obstruction. The patients were aged between 40 and 82 years, with the primary located in the distal transverse colon (2) and descending colon (1). All patients required intervention for obstruction, with two undergoing surgical resection and one endoscopic stenting. The two surgical specimens demonstrated near complete or complete pathological response in the primary, with replacement of the tumour bed by fibrosis or fibrofatty inflammatory tissue. Predisposing factors in our case series included tumours unable to be traversed at diagnosis with colonoscopy and radiologic evidence of a bulky primary or stenotic lesion. Our case series suggests that a truly excellent response to immunotherapy may result in the development of obstruction secondary to complete replacement of the primary with fibrotic tissue resulting in a high-grade benign stricture. Conclusion These cases highlight the importance of multi-disciplinary management of dMMR colon cancer patients and the need for monitoring of obstructive symptoms during immunotherapy in high-risk patients.