Background <p>There is an important need to develop clinical strategies to reduce the risk of incident kidney cancer, especially in patients with type 2 diabetes (T2D) often accompanied by chronic kidney disease. Here, we investigated whether sodium-glucose cotransporter 2 (SGLT2) inhibitor use is associated with reduced kidney cancer risk compared to dipeptidyl peptidase-4 (DPP-4) inhibitor use in patients with T2D, using a nationwide cohort of the Korean national health insurance claims and health examination database.</p> Methods <p>After 1:1 propensity score matching, 57,103 SGLT2 inhibitor new users and 57,103 DPP-4 inhibitor new users were selected from 581,702 kidney cancer-free participants, aged 20 to 79 years, who started oral glucose-lowering drugs for T2D from 2014 to 2018.</p> Results <p>During 408,481 person-years of follow-up, 102 (25.0 per 100,000 person-years) new kidney cancer events occurred. SGLT2 inhibitor use was associated with a 40% reduced risk of kidney cancer compared with DPP-4 inhibitor use (18.9 vs. 30.8 per 100,000 person-years; hazard ratio [HR] 0.60, 95% CI 0.40 to 0.89). The reduced kidney cancer risk associated with SGLT2 inhibitor use versus DPP-4 inhibitor use was consistent even after additional adjustment for all variables composing the propensity scores (HR 0.60, 95% CI 0.40 to 0.90) and regardless of age, sex, body mass index, current smoking, hypertension, medication use, or diabetic complications including nephropathy (all <i>p</i> &gt; 0.05 for interaction). When comparing SGLT2 inhibitor users with 1:1 propensity score-matched non-users, SGLT2 inhibitor use was associated with a 34% reduced risk of kidney cancer compared to non-use (HR 0.66, 95% CI 0.49 to 0.89).</p> Conclusions <p>Our findings suggest a potential association between SGLT2 inhibitor use and a lower risk of kidney cancer, which needs to be further validated.</p> Graphical Abstract <p></p>