PURPOSE: To examine potential overall survival (OS) differences between males and females with advanced gastric (GAC), gastroesophageal junction (GEJAC) and esophageal (EAC) adenocarcinoma. PATIENTS AND METHODS: The study included patients from Kaiser Permanente Northern California with de novo metastatic or relapsed EAC, GEJAC and GAC. We used Cox regression modeling to examine association of sex with OS adjusting for demographics, performance status, Charlson comorbidity index, histology (Lauren's classification), receipt of chemotherapy, and HER2 amplification or overexpression, p53, KRAS, CDKN2A, PIK3CA co-mutations and MYC amplification. RESULTS: Of 875 total eligible patients, 426 had GAC, of whom 224 were male and 202 were female. Among patients with GAC, males had better OS than females (HR = 0.73; [95% CI, 0.59-0.92]), and this OS difference was preserved across the molecular subgroups except mutKRAS. Intriguingly, among GAC patients with a p53 mutation, males versus females had better OS if tumor carried a non-gain-of-function mutation (non-GOF, HR = 0.59; [95% CI, 0.40-0.85]) but worse OS if tumor carried gain-of-function mutation (GOF, HR = 1.80; [95% CI, 0.83-3.99]). Sex was not associated with OS among patients with GEJAC (HR = 1.14); (95% [CI, 0.77-1.67]) or EAC (HR = 1.0; [95% CI, 0.57-1.74]). These results remained similar when separate analyses were performed among patients who received and among patients who did not receive chemotherapy. CONCLUSIONS: Males had better OS than females among patients with advanced GAC. In addition, among GAC patients with a mutp53, sex and OS association was inversely driven by the presence of GOF versus non-GOF. Our data reveal a previously unappreciated sex disparity in survival outcomes among patients with advanced GAC. If confirmed, this finding could have important implications for clinical practice and for further understanding the biology of GAC.