Background: PM from GC or GEJ portend a poor prognosis and molecular differences are ill defined. Methods: We compared genomic profiles of primary (P) GC and GEJ with PM patients (pts) and other metastases (OM) sent to Caris Life Sciences. Testing comprised immunohistochemistry (IHC) including programmed death ligand 1 (PD-L1) combined positive score (CPS), copy number alterations (CNA), 592-gene next-generation sequencing (NGS), microsatellite instability (MSI) and tumor mutational burden (TMB). Results: 1366 cases were identified: 1041 GC (707 P, 98 PM, 236 OM) and 325 GEJ (248 P, 5 PM, 72 OM). PM were increased in GC versus GEJ (9% v. 2%, p < 0.0001). 91% GC and 93% GEJ were adenocarcinoma (AD); GC were more likely signet ring (SR) histology versus GEJ (11% v. 3%, p < 0.0001) and GC PM were more likely SR versus other OM or P (13% v. 12% v. 7%, p = 0.067). The mean age of PM pts (57 years) was younger than primary GC (63, p = 0.002) and OM (61; p = 0.044). More PM GC pts were female than P or OM (48% v. 35% v. 34%, p = 0.03). No molecular profiling differences were seen between GEJ and GC pts and they were combined for analysis; findings from 1246 AD pts are shown below (see Table). OM (9%, p = 0.041) had more CNA in CCNE1 than PM (2%, p = 0.041) or P (5%, p = 0.002). Conclusions: Compared to P and OM GC, PM pts were younger, more likely female and had a higher incidence of SR histology. PD-L1, HER2 IHC and ERBB2 CNA were reduced in PM versus P, suggesting novel therapeutic targets are needed.