Background:　This　study　aims　to　investigate　the　differences　in　postoperative　prognosis　associated　with　the　single　nucleotide　polymorphism　(SNP)　rs2228226　(G　＞　C)　in　gastric　adenocarcinoma　(GAC)　patients.　Methods:　This　study　enrolled　661　patients　with　locally　advanced　(pT4a)　GAC　after　surgery.　DNA　was　extracted　from　their　tissues　and　genotyped　for　rs2228226　using　a　MassARRAY　Analyzer.　Based　on　the　patients’　clinical　and　pathological　information,　a　multifactorial　Cox　regression　analysis　was　performed　to　assess　the　correlation　between　rs2228226　and　the　clinical　prognosis　of　pT4a　GAC　patients.　Survival　differences　among　patients　who　received　postoperative　chemotherapy　were　also　examined　according　to　rs2228226.　Results:　After　excluding　patients　with　distant　metastasis,　loss　to　follow-up,　and　those　not　meeting　the　inclusion　criteria,　a　total　of　463　patients　with　complete　data　were　included.　The　rs2228226　genotype　distribution　was　as　follows:　C/C　=　57　(12.3%),　G/C　=　200　(43.2%),　and　G/G　=　206　(44.5%).　Patients　with　the　C/C　genotype　had　significantly　shorter　disease-free　survival　(DFS　=　12 months)　and　overall　survival　(OS　=　27 months)　compared　to　those　with　the　G/C　or　G/G　genotype　(DFS　=　19 months,　log-rank　P　=　0.003;　OS　=　35 months,　log-rank　P　=　0.002).　Further　analysis　of　patients　receiving　chemotherapy　identified　the　C/C　genotype,　advanced　age,　lymph　node　metastasis,　degree　of　differentiation,　and　failure　to　achieve　R0　resection　as　independent　risk　factors　for　tumor　recurrence　and　metastasis　(P　＜　0.05).　The　C/C　genotype,　lymph　node　metastasis,　and　tumor　recurrence　and　metastasis　were　independent　risk　factors　for　mortality　(P　＜　0.05).　Conclusions:　In　pT4a　GAC　patients　undergoing　postoperative　chemotherapy,　the　C/C　genotype　at　rs2228226　is　an　independent　risk　factor　for　tumor　recurrence,　metastasis,　and　death.　The　rs2228226　(G　＞　C)　polymorphism　may　serve　as　a　potential　biomarker　for　predicting　prognosis　after　chemotherapy　in　GAC.　©　The　Author(s)　2025.