Objective: To investigate the genes and signaling pathways associated with the sensitivity of advanced gastric cancer to S-1 plus oxaliplatin (SOX) neoadjuvant chemotherapy. Methods: The surgical specimens from 15 patients with stage III gastric cancer were collected, in which, 6 cases responded (responder group) and 6 cases did not respond (non-responder group) after SOX neoadjuvant chemotherapy, and 3 cases did not receive any neoadjuvant chemotherapy (non-chemotherapy group). After the gene expression profile in each group was detected by high-throughput gene microarray screening, choosing DNA damage repair and folate metabolism as two major analytical aspects, the differentially expressed genes were screened by systemic bioinformatics analysis, and then, pathways associated with the differentially expressed genes were identified through KEGG mapping. Results: There was an obvious different gene expression profiles among the three groups of specimens. The differentially expressed genes between responder group and non-responder group were highly enriched in pathways relevant for cytokine-cytokine interactions and cytotoxicity mediated by NK cells. Of the genes associated with DNA damage repair, three (HUS1, RECQL5 and XRCC4) were up-regulated and one (GADD45G) was down-regulated significantly in responder group compared with non-responder group; no differentially expressed gene related to folate metabolism was found among the three groups. Conclusion: The genes affecting the sensitivity of advanced gastric cancer to SOX neoadjuvant chemotherapy may be associated with immune signal transduction, and the detection of the relevant genes may have certain significance for estimating the efficacy of SOX neoadjuvant chemotherapy for gastric cancer.