BACKGROUND: A sizeable number of individuals who participate in population-based colorectal cancer (CRC) screening programs and have a positive fecal occult blood test (FOBT) do not have an identifiable lesion found at colonoscopy to account for their positive FOBT screen.OBJECTIVE: To evaluate the evidence and provide recommendations regarding the use of routine esophagogastroduodenoscopy (EGD) to detect upper gastrointestinal (UGI) cancers in patients participating in a population-based CRC screening program who are FOBT positive and colonoscopy negative.METHODS: A systematic review was used to develop the evidentiary base and to inform the evidence-based recommendations provided.RESULTS: Nine studies identified a group of patients who were FOBT positive and colonoscopy negative. Three studies found no cases of UGI cancer. Four studies reported cases of UGI cancer; three found UGI cancer in 1% or less of the population studied, and one study found one case of UGI cancer that represented 7% of their small subgroup of FOBT-positive/colonoscopy-negative patients. Two studies did not provide outcome information that could be specifically related to the FOBT-positive/colonoscopy-negative subgroup.CONCLUSION: The current body of evidence is insufficient to recommend for or against routine EGD as a means of detecting gastric or esophageal cancers for patients who are FOBT positive/colonoscopy negative, in a population-based CRC screening program. The decision to perform EGD should be individualized and based on clinical judgement.