Background and Aim <p>PNPLA3 rs738409 reduces the triglyceride hydrolase activity. This systematic review and meta-analysis aimed to assess the association between PNPLA3 rs738409 polymorphism and the risk of liver cirrhosis across various etiologies.</p> Methods <p>Potential articles were selected from PubMed, Embase, Cochrane Library, and Web of Science databases, guided by well-defined inclusion and exclusion criteria. The quality of each article was rigorously evaluated using the Newcastle-Ottawa Scale (NOS). Association between PNPLA3 rs738409 and liver cirrhosis was expressed in terms of odds ratios (ORs) accompanied by 95% confidence intervals (CIs).</p> Results <p>This meta-analysis encompassed 21 studies (22 tests, comprising 79102 controls and 4006 cases). The aggregate findings revealed a notable positive correlation between the rs738409 and the risk of liver cirrhosis across all genetic models: G vs. C (OR = 1.75, 95% CI = 1.64–1.86), GC vs. CC (OR = 1.77, 95% CI = 1.61–1.94), GG vs. CC (OR = 2.69, 95% CI = 2.34–3.08), GG vs. CG + CC (OR = 2.02, 95% CI = 1.79–2.28), and GG + CG vs. CC (OR = 1.99, 95% CI = 1.82–2.17). There was a pronounced heterogeneity observed across all genetic models, and might be induced by race and control groups. Subgroup analyses showed significant association respectively in Caucasian and Asian, as well as healthy controls, ALD and other liver diseases control types.</p> Conclusion <p>PNPLA3 rs738409 polymorphism has been robustly linked to an increased risk of etiology-specific liver cirrhosis.</p>