Background: JCOG1013, a phase III study comparing CS therapy with DCS therapy for AGC, failed to demonstrate the superiority of DCS to CS in overall survival (OS) (Yamada Y, Lancet GH 2019). Because cisplatin and gimeracil (an inhibitor of dihydropyrimidine dehydrogenase contained in S-1) are excreted in urine, it is speculated that renal dysfunction may affect the safety and efficacy of CS and DCS in patients (pts) with AGC. Methods: Among 741 all randomized pts, pts with serum creatinine level < 1.2 mg/dL were included in this study. Pts were categorized by creatinine clearance (CrCl) and treatment into A1 (CrCl ≥ 80 mL/min, CS), A2 (60 < CrCl < 80, CS), A3 (CrCl < 60, CS), B1 (CrCl ≥ 80, DCS), B2 (60 < CrCl < 80, DCS), and B3 (CrCl < 60, DCS). Adverse events, OS, progression-free survival (PFS), objective response rate (ORR) were compared by CrCl in group A (A1 vs. A2 vs. A3) and group B (B1 vs B2 vs B3), respectively, and between the treatment groups according to CrCl (A1 vs. B1, A2 vs. B2, A3 vs. B3). Results: Of 723 pts (169/136/57 in A1/A2/A3 and 170/138/53 in B1/B2/B3), the median CrCl was 94.1/71.9/53.4 mL/min in A1/A2/A3 and 98.2/70.0/55.6 mL/min in B1/B2/B3 group. The incidence of Grade (G) 4 hematological toxicity was 7.8/16.3/25.9% in A1/A2/A3 (P < 0.01), and 29.1/29.3/22.0% in B1/B2/B3 (P = 0.44), and that of G3-4 non-hematological toxicity was 46.1/64.4/64.3% in A1/A2/A3 (P < 0.01) and 54.6/64.7/74.5% in B1/B2/B3 (P < 0.01), respectively. The median OS was 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.89) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.72). The median PFS was comparable in A1/A2/A3 (7.1/6.8/6.2 months, P = 0.88) and B1/B2/B3 groups (7.5/7.2/7.8 months, P = 0.85). ORR showed no significant difference in A1/A2/A3 (58.9/57.8/46.9%, P = 0.31) and B1/B2/B3 groups (62.0/61.5/51.5%, P = 0.36). Comparisons between treatment arms according to CrCl (A1 vs. B1, A2 vs. B2, A3 vs. B3) did not show any significant difference in OS (P = 0.88, 0.65, 0.83) and PFS (P = 0.91, 0.63, 0.46). Conclusions: In this exploratory analysis of JCOG1013, CrCl might be associated with safety (G4 hematological toxicity for CS, and G3-4 non-hematological toxicity for CS and DCS), but not with efficacy in either group. Clinical trial information: 000007652.