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Pyogenic liver abscess (PLA) is a life-threatening infection rising in East Asia, especially among patients with type 2 diabetes. Although SGLT2 inhibitors improve glycemic control and offer extraglycemic benefits, their effect on PLA risk is unknown. Using Taiwan's National Health Insurance Research Database, we conducted a nationwide retrospective cohort study of adults with T2DM. After 1:1 propensity score matching, 258,800 SGLT2i users and 258,800 non-users were included. The primary outcome was incident PLA. Incidence rates were calculated per 1,000 person-years, and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using multivariable Cox proportional hazards models. Additional analyses included subgroup analyses with interaction testing, a time-dependent Cox model, a competing-risks model, and a negative-control outcome analysis using fracture. During follow-up, 1,275 PLA events were identified. The incidence rate of PLA was 0.75 per 1,000 person-years in SGLT2i users and 0.83 per 1,000 person-years in non-users. In the primary multivariable Cox model, SGLT2i use was associated with a lower risk of PLA compared with nonuse (aHR, 0.88; 95% CI, 0.79-0.99). This inverse association was generally consistent across most subgroups. In the time-dependent analysis, SGLT2i use remained associated with a lower PLA risk (aHR, 0.72; 95% CI, 0.64-0.81). SGLT2i therapy was independently associated with reduced PLA risk in T2DM patients, particularly with prolonged exposure. These findings suggest an inverse association between SGLT2i use and the risk of pyogenic liver abscess in patients with T2DM.