AIMS: To investigate the clinical significance of the modification of the kidney protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors by baseline body mass index (BMI). METHODS AND RESULTS: We included individuals with SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP4) inhibitors newly prescribed for type 2 diabetes using a nationwide epidemiological cohort and performed propensity score matching (1:2). The primary outcome was the annual eGFR decline, assessed using a linear mixed-effects model, compared between individuals with SGLT2 inhibitors and DPP4 inhibitors. We investigated the interaction effect of BMI at the time of prescription using a three-knot restricted cubic spline model. We analysed 2165 individuals with SGLT2 inhibitor prescriptions and 4330 individuals with DPP4 inhibitor prescriptions. Overall, the annual decline in eGFR was less pronounced in the group treated with SGLT2 inhibitors than in those treated with DPP4 inhibitors (-1.34 mL/min/1.73 m2 vs. -1.49 mL/min/1.73 m2). The advantage of SGLT2 inhibitors in mitigating eGFR decline was augmented in the individuals with higher BMI (P-value for interaction 0.0017). Furthermore, even upon adjusting the definition of outcomes to encompass a 30 or 40% reduction in eGFR, the potential advantages of SGLT2 inhibitors over DPP4 inhibitors persisted, with a trend of augmented effects with higher BMI. This interaction effect was evident in the individuals with preserved kidney function. CONCLUSION: Our nationwide epidemiological study substantiated the improved kidney outcomes in the SGLT2 inhibitor users compared with the DPP4 inhibitor users across a wide range of BMI, which was pronounced for individuals with higher BMI.