Abstract Background Hereditary diffuse gastric cancer (HDGC) is predominantly attributed to CDH1 [E-Cadherin] germline mutation and carries a cumulative lifetime risk of diffuse gastric cancer (DGC) of up to 70%. Definitive treatment remains prophylactic total gastrectomy (PTG) with an attendant risk of morbidity and reduced quality of life. Endoscopic surveillance following the Cambridge protocol is an alternative for selected patients, however, the impact on disease stage and long-term gastric cancer prognosis is not established. This study aims to evaluate clinical and histopathological outcomes following PTG in patients with germline CDH1 mutations with or without prior surveillance at a national HDGC referral centre. Methods Retrospective review was performed of clinicopathological outcomes for germline CDH1 mutation carriers who underwent PTG at Addenbrooke’s Hospital between January 2006 and May 2023. Indication for surgery of clinical stage 1 tumours was guided by patient preference, multiple visible lesions and increasing number of signet ring cell (SRC) foci. Endoscopic surveillance was offered to cases with no concerning endoscopic lesion and low number of SRC foci. Patients with confirmed DGC (≥stage 2) at diagnosis were excluded. Standard PTG procedure was open TG with D1 lymphadenectomy and preservation of posterior vagus with D2 lymphadenectomy and truncal vagotomy in selected cases. Results 48 patients underwent open PTG with D1 (93.8%) or D2 (6.2%) lymphadenectomy. PTG was deferred in 18 patients (37.5%) with median of 3 pre-operative surveillance endoscopies over 22 months (5 to 61 months). Median post-operative length of stay was 7 days (6 to 12). Major morbidity was observed in 1 case (2.1%) with no post-operative mortalities. Final stage was pT1aN0M0 in 43 patients (89.6%) and pT0N0M0 in 5 patients (10.4%). No lymph node metastases were observed and complete gastric mucosal resection was achieved for all. The 5-year estimated overall and disease-specific survival were 100% with median follow-up of 7 years. Conclusions PTG remains a robust and effective treatment for patients with pathogenic germline CDH1 mutations who are appropriate surgical candidates. There was no increase in final stage following surveillance in a dedicated specialist service and this remains a safe alternative in selected cases. For patients choosing to proceed with PTG following comprehensive pre-operative counselling, this can be undertaken with low morbidity in a specialist centre. Further long-term data are needed to determine the impact of surgery and endoscopic surveillance on survival, functional outcomes and quality of life.