Purpose: Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. The present study analyzed the polymorphism of lipoprotein-related receptor 5(LRP5)(gene with key functions in Wnt signaling) and its impact on the response to chemotherapy and survival of patients with advanced gastric cancer(AGC).Methods: A total of 107 consecutive patients with AGC treated with first-line chemotherapy of EOF regimen were enrolled in the present retrospective study. The association between single nucleotide polymorphism(SNP) of rs3736228 in LRP5 and the clinical outcomes of the patients was studied.Results: The CC genotype of rs3736228 was significantly correlated with a higher disease control rate when compared to the CT and TT genotypes(89.3% and 61.8%, respectively, P<0.001). A univariate survival analysis also showed that the progression free survival(PFS) and overall survival(OS) for the patients with the TC and TT genotypes of rs3736228 were worse than for the patients with the CC genotype(PFS: 3.3 and 6.7 months, respectively, HR =0.454, P<0.001; OS: 8.1 months and 18.8 months, respectively, HR =3.056, P<0.001). A multivariate Cox model incorporates rs3736228 and clinical features, also identified rs3736228 was significantly associated with the PFS and OS.Conclusions: Our results firstly highlight the importance of LRP5 gene of Wnt pathway in the treatment of AGC and identify polymorphism of rs3736228 as independent predictor of disease control rate, PFS and OS in AGC patients treated with first-line chemotherapy of EOF regimen in the Chinese Han population. Purpose: Wnt pathways control key biological processes that potentially study on tumor progression and patient survival. The present analysis analyzed the polymorphism of lipoprotein-related receptor 5 (LRP5) (gene with key functions in Wnt signaling) and its impact on the response to chemotherapy and survival of patients with advanced gastric cancer (AGC). Methods: A total of 107 consecutive patients with AGC treated with first-line chemotherapy of EOF regimen were enrolled in the present retrospective study. The association between single nucleotide polymorphism (SNP) of rs3736228 in LRP5 and the clinical outcomes of the patients were studied. Results: The CC genotype of rs3736228 was significantly correlated with a higher disease control rate when compared to the CT and TT genotypes (89.3% and 61.8% respectively, P <0.001). A univariate survival analysis also showed that the progression free survival (PFS) and overall survival (OS) for the patients with the TC and TT genotypes of rs3736228 were worse than for the patients with the CC genotype (PFS: 3.3 and 6.7 months, respectively, HR = 0.454, P <0.001 OS: 8.1 months and 18.8 months, respectively, HR = 3.056, P <0.001). A multivariate Cox model incorporates rs3736228 and clinical features, also identified rs3736228 was significantly associated with the PFS and OS.Conclusions: Our results hereby highlight highlight the importance of LRP5 gene of Wnt pathway in the treatment of AGC and identify polymorphism of rs3736228 as independent predictor of disease control rate, PFS and OS in AGC patients treated with first-line chemotherapy of EOF regimen in the Chinese Han population.