OBJECTIVE: This meta-analysis is to investigate the relationship between the patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 polymorphism and the susceptibility and severity of nonalcoholic fatty liver disease (NAFLD). METHODS: Chinese Journal Full-text Database, Wanfang Database, VIP Database, and PubMed Database were subjected to case-control study retrieving, from January 2008 to December 2014. Following key words were used: fatty liver, PNPLA3, and rs738409 gene or variants or polymorphism or alleles. Meta-analysis was performed based on the retrieved articles. RESULTS: In total 65 studies were first retrieved according to the key words, and finally 21 studies with 14,266 subjects were included. Meta-analysis showed that PNPLA3 rs738409 polymorphism exerted strong influence not only on fatty liver but also on the histological injury. PNPLA3 rs738409 [G] allele was a risk factor for NAFLD (GG vs CC, OR = 4.01, 95% CI 2.93-5.49; GC vs CC, OR = 1.88, 95% CI 1.58-2.24). PNPLA3 gene variant was significantly associated with the increased serum alanine aminotransferase (ALT) levels (GG vs CC, standardized mean difference  = 0.47, 95% CI 0.14-0.81). In addition, nonalcoholic steatohepatitis (NASH) was more frequently observed in G allele carriers (GG vs CC, OR = 3.24, 95% CI 2.79-3.76; GC vs CC, OR = 2.14, 95% CI 1.43-3.19). CONCLUSION: PNPLA3 rs738409 polymorphism is not only a factor significantly associated with the susceptibility of NAFLD, but also related to the susceptibility of aggressive diseases.