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Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome causing intestinal polyposis and a high risk of early onset gastrointestinal, brain, and hematological cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. Aim: Our aim was to determine if surveillance affects outcome. The primary outcome measure was overall survival. The secondary outcome measure was detection of new cancers. Methods: Patients referred to the International Replication Repair Consortium undergo genetic testing to confirm CMMRD. All individuals were diagnosed with CMMRD through diagnostic criteria by the genetic counsellor at the consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging studies was recommended and initiated internationally on Jan 1, 2012. Protocol included upper endoscopy, colonoscopy, video capsule endoscopy and/or magnetic resonance enterography, and brain MRI. Whole-body MRI was recommended as of Jan 1, 2018. Surveillance questionnaire was sent to the responsible physician with diagnostic fields completed by the registry coordinator as a double check of reliability. Survival analyses was completed using an as-treated approach. Results: Cancer and surveillance data was collected from 64 (50%) of 127 CMMRD individuals registered in the Consortium from 41 countries. There were 114 tumours reported in 60 patients including 55 brain, 28 gastrointestinal (GI), 17 hematological and 14 other malignancies. Surveillance data was available on 110 cancers; 16 were incidental cancers, 68 were symptomatic and 26 were discovered through surveillance. Surveillance identified 13 GI cancers, 11 brain, and 2 hematological malignancies. The gastrointestinal cancers included 5 colorectal, 7 small bowel, and one gastric. Four patients were unaffected. Five-year overall survival was 95% for tumors discovered by surveillance, compared to 43% for symptomatic tumors (p=0.001). Overall survival for gastrointestinal tumors identified by surveillance was 100% (n=13) compared to 79% (n=19) for symptomatic lesions (p=0.1). Similarly, 5-year survival was 83+/-15% and 32+/-7% for surveillance and non-surveillance of brain tumors (p=0.03). Median age at diagnosis of gastrointestinal cancer was 14.6 years (range 9.0-50.6 years). Conclusion: These data support a survival benefit in CMMRD patients undergoing a surveillance protocol.