Background: Gastric cancer (GC) is the second most common non-gynecologic malignancy in patients with LS. Due to an absence of prospective randomized data, the value of esophago-gastro-duodenoscopy (EGD) for GC surveillance in LS patients remains a controversial issue. According to German guidelines regular EGDs beginning at the age of 35 are recommended for LS patients. The focus of this study was to evaluate the effectiveness of EGD as an instrument for early GC detection. Methods: Data of HNPCC and LS patients diagnosed with GC was retrieved from the German Consortium for Familial Intestinal Cancer Registry. Individuals from 3 groups were included: pathogenic germline mismatch repair gene mutation carriers (n = 47), untested patients from families with known germline mutations (putative carriers; n = 8) and individuals fulfilling at least the revised Bethesda criteria without a mutation but with microsatellite instability (MSI group; n = 47). Statistics were calculated using Fisher’s exact test. Results: Overall a total number of 107 GCs were observed in 102 patients (male/female: 60/42) with 71 (69%) having a negative family history of GC. Among germline mutation carriers, MLH1 (n = 21) and MSH2 (n = 24) mutations were the most prevalent; EPCAM and MSH6 mutations were rare with only one case each. The median age at diagnosis was 54.4 years (28.9-81.4) for the whole cohort, with mutation carriers being diagnosed at a younger age (51.8 years) than individuals from the MSI group (63.1 years). Of all GC patients, two were diagnosed at an age younger than 35 years and 7 patients were younger than 40 years. The GCs in patients undergoing surveillance were diagnosed significantly more often with an early stage disease (UICC I) than GCs detected through symptoms (77.8% vs. 23.5%; p = 0.0046). Conclusions: To our knowledge this is the largest study investigating the effectiveness of EGD surveillance for early GC detection in HNPCC or LS patients. This study indicates a benefit for patients undergoing regular EGDs and supports the recommendation of regular gastroscopic surveillance for HNPCC and LS syndrome patients beginning not later than at the age of 35.