The 2-week S-1/LV regimen demonstrated promising efficacy and satisfactory safety as first-line chemotherapy for AGC. To balance both the efficacy and toxicity, S-1 pharmacogenetic pathway may help find an optimal subset of patients with high OPRT/TS, high AUC0–24h of 5-FU, low DPD that may benefit more from S-1/LV, which awaits validation in another large and well-defined population.