A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, the PNPLA3 single-nucleotide polymorphism rs738409 (M148I) was reported to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of Mestizo descent. We therefore evaluated the impact of rs738409 on the manifestation of alcoholic liver disease in two independent German cohorts. Genotype and allele frequencies of rs738409 (M148I) were determined in 1,043 alcoholic patients with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Relative to alcoholic patients without liver damage (n 5 439), rs738409 genotype GG was strongly overrepresented in patients with alcoholic liver cirrhosis (n 5 210; OR 2.79; P genotype 5 1.2 3 10 25 ; P allelic 5 1.6 3 10 26 ) and in alcoholic patients without cirrhosis but with elevated alanine aminotransferase levels (n 5 219; OR 2.33; P genotype 5 0.0085; P allelic 5 0.0042). The latter, biochemically defined association was confirmed in an independent population-based cohort of at-risk drinkers with a median alcohol intake of 300 g/ week (OR 4.75; P genotype 5 0.040; P allelic 5 0.022), and for aspartate aminotransferase (AST) levels. Frequencies of allele PNPLA3 rs738409(G) in individuals with steatosis and normal alanine aminotransferase (ALT) and AST levels were lower than in alcoholics without steatosis and normal ALT/AST (P combined 5 0.03). The population attributable risk of cirrhosis in alcoholic carriers of allele PNPLA3 rs738409(G) was estimated at 26.6%. Conclusion: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians. (HEPATOLOGY 2011;53:86-95) A lcoholic liver disease (ALD) accounts for over 50% of all chronic liver disease in industrialized countries 1-3 and was responsible for more than 25,000 deaths in 2005 in the United States alone. 4 ALD comprises various degrees of liver injury ranging from alcoholic fatty liver (with or without inflammation) to alcohol-induced hepatic fibrosis and cirrhosis.