One of the potential partners of S-1 is leucovorin (LV), known to enhance the efficacy of 5-FU by forming a ternary complex with 5-FU metabolite and thymidylate synthase (TS) which prolongs the inhibition of TS and blocks DNA synthesis. It was proved UFT, a third-generation oral 5-FU, had favorable activity and tolerability when combined with LV in AGC patients . A phase II study of S-1 plus LV (S-1/LV) has demonstrated promising efficacy and acceptable safety in patients with metastatic colorectal cancer (mCRC) . A randomized phase II study reported promising efficacy of S-1/LV and S-1/LV plus oxaliplatin (SOL) for AGC, compared with S-1 plus cisplatin . However, there has been no one-arm phase I/II study for S-1/LV in gastric cancer patients. Interindividual variation in pharmacogenetics of the S-1 metabolic pathway can affect the extent of S-1 metabolism and impact the efficacy and toxicity of S-1-based chemotherapy. Published studies all used “candidate” pharmacogenetic factors to predict the outcomes of AGC patients with S-1 or S-1-based chemotherapy, none of which used S-1 pharmacogenetic pathway approach, which means none integrated CYP2A6 polymorphism, 5-FU metabolic enzymes, and pharmacokinetics at the same time [6–8]. However, those factors do not act in isolation. What is more, the results and methods varied across studies. Finally, predictive values of these candidates might or might not be overcome with drugs combined with S-1.