Abstract Body (Do not enter title and authors here): Background: Direct-acting oral anticoagulants (DOACs) have emerged as a preferred alternative to Vitamin K Antagonists (VKAs) for patients with atrial fibrillation (AF). However, the exclusion of patients with liver cirrhosis (LC) from recent clinical trials leaves the efficacy and safety of DOACs in this population unclear. Hypothesis: DOACs are more effective and have a better safety profile compared to VKAs in patients with AF and LC. Methods: Following the PRISMA guidelines, we searched PubMed, Cochrane Library, Embase, Scopus, Web of Science, and CNKI databases for randomized clinical trials (RCTs) and observational studies comparing DOACs and VKAs in patients with AF and LC. Statistical analysis was performed using the metafor package in R software. Heterogeneity was assessed using the I2 statistic, and a random-effects model was employed to calculate pooled Hazard Ratios (HRs). For trivial heterogeneity (I2<25%), a fixed-effect model was used. The confidence interval (CI) was set at 95%. Results: A total of one RCT and eight observational studies, encompassing 21903 patients, were included. Of these, 9882 patients were treated with DOACs and 11211 with VKAs. In 10105 patients with AF and LC, the incidence of major bleeding events was significantly lower in the DOAC group compared to the VKA group (HR 0.64; 95%CI 0.55-0.74; p<0.001; I2=0%) (Figure 1A). The pooled adjusted effect estimates from multivariable analysis and inverse probability weighting for major bleeding were consistent (HR 0.71; 95%CI 0.61-0.82; p<0.001; I2=7%) (Figure 1B). Additionally, the DOAC group exhibited lower rates of gastrointestinal (GI) bleeding (HR 0.76; 95%CI 0.69-0.85; p<0.001; I2=18%) and intracranial hemorrhage (ICH) (HR 0.71; 95%CI 0.59-0.85; p<0.001; I2=0%). There were no significant differences in thromboembolic events (Figure 2A) and all-cause mortality (Figure 2B) between the groups. Meta-regression analyses showed no significant impact of age, sex, follow-up duration, or baseline antiplatelet therapy on major bleeding events. Conclusion: In patients with AF and LC, DOACs are associated with a safer bleeding profile compared to VKAs, showing a reduced risk of major bleeding, GI bleeding, and ICH. However, no significant differences were observed in thromboembolic events or all-cause mortality. These findings suggest the potential of DOACs as a safer alternative in this patient population, warranting further validation through well-designed clinical studies.