AIM: Various subcategories for steatotic liver disease (SLD) were proposed globally. Previous studies suggested a heightened risk of cardiovascular diseases (CVD) with prolonged antibiotic exposure and metabolic dysfunction-associated SLD (MASLD), respectively. This study investigates the impact of antibiotic usage on CVD in MASLD patients. METHODS: From the Korean National Health Insurance Service database, 276 520 adults aged 40 and older were included. Antibiotic exposure was defined by the cumulative prescription days and the number of classes. Participants were categorized into no SLD and MASLD groups. Hepatic steatosis was defined by using the fatty liver index ≥60. From 2013 to 2019, 16 197 CVD cases were recorded. A multivariate Cox model, adjusting for covariates, assessed adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for CVD risk associated with MASLD and antibiotic prescriptions. RESULTS: The group with ≥91 days of antibiotics prescribed and MASLD showed a significantly increased risk of CVD (aHR, 1.56; 95% CI, 1.39-1.74) compared with antibiotic non-users without SLD. Furthermore, the group with ≥4 classes of antibiotics prescribed and MASLD had an elevated risk of CVD (aHR, 1.49; 95% CI, 1.34-1.66) compared with antibiotic non-users without SLD. Consistent results were observed in several sensitivity analyses. CONCLUSIONS: Our study identified prolonged antibiotic exposure may be a factor that increases the risk of CVD in MASLD patients. These findings suggest an epidemiological basis for the therapeutic application of antibiotics in MASLD patients, and emphasize the need for further studies to deepen the understanding of these intricate relationships.