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Introduction Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), commonly co-occurs with type 2 diabetes mellitus (T2DM) and increases risks of cardiometabolic and hepatic complications. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) and dipeptidyl peptidase-4 inhibitors (DPP4is) are commonly prescribed antidiabetic agents with potential hepatic benefits, yet large-scale, real-world head-to-head comparisons in patients with MASLD are limited.Methods This multicenter, retrospective cohort study utilized de-identified electronic health records from the TriNetX U.S. Collaborative Network. Adults (≥18 years) with MASLD, and at least one metabolic comorbidity (T2DM, obesity, dyslipidemia, metabolic syndrome, or hypertension) were included. Patients newly initiating SGLT2is (n=111,357; e.g., empagliflozin, dapagliflozin, canagliflozin) or DPP4is (n=43,868; e.g., sitagliptin, linagliptin) without cross-exposure were identified. One-to-one propensity score matching (caliper 0.1 SD) balanced cohorts at 41,793 patients each, using >50 covariates (demographics, comorbidities, medications, laboratories, vitals). Time-to-event analyses for all-cause mortality, all-cause hospitalization, major adverse cardiovascular events (MACE), major adverse liver outcomes (MALO), major adverse kidney events (MAKE), ascites, hepatic failure, and hepatic encephalopathy were performed at 1-year and 3-year follow-up using Cox proportional hazards models.Results In propensity-matched cohorts, SGLT2is were associated with significantly lower risks compared to DPP4is for: All-cause mortality (1-year HR 0.746, 95% CI 0.674–0.825; 3-year HR 0.778, 95% CI 0.725–0.834); MAKE (1-year HR 0.316, 95% CI 0.281–0.355; 3-year HR 0.419, 95% CI 0.383–0.459); MALO (1-year HR 0.837, 95% CI 0.742–0.944; 3-year HR 0.856, 95% CI 0.780–0.940); Ascites (1-year HR 0.761, 95% CI 0.660–0.879; 3-year HR 0.823, 95% CI 0.738–0.919). All-cause hospitalization showed modest benefit at 1 year (HR 0.951, 95% CI 0.921–0.982) but neutrality at 3 years (HR 1.011, 95% CI 0.984–1.039). Conversely, MACE risk was higher with SGLT2is (1-year HR 1.225, 95% CI 1.158–1.295; 3-year HR 1.171, 95% CI 1.119–1.226). No significant differences emerged for hepatic failure or hepatic encephalopathy.Conclusions In this large, multicenter, propensity score-matched real-world cohort of patients with MASLD, initiation of SGLT2is conferred superior protection against all-cause mortality, major kidney events, major liver events, and ascites compared with DPP4is, with the strongest benefits observed in renal outcomes. While hospitalization benefits were short-term and MACE rates were modestly higher with SGLT2is, these findings support preferential consideration of SGLT2is in MASLD patients requiring antidiabetic therapy.Abstract FP25 Figure 1