The study investigates genetic variants contributing to differences in hepatic fat content and susceptibility to nonalcoholic fatty liver disease (NAFLD) across different ethnic groups. A genome-wide association scan identified an allele in *PNPLA3* (rs738409; I148M) strongly associated with increased hepatic fat levels and inflammation (P=5.9×10−10 and P=3.7×10−4, respectively). This allele was most prevalent in Hispanics, who have the highest prevalence of NAFLD. Resequencing revealed another allele (*PNPLA3*-S453I) associated with lower hepatic fat content in African-Americans, the group with the lowest risk of NAFLD. These findings suggest that variation in *PNPLA3* contributes to ethnic and individual differences in hepatic fat content and susceptibility to NAFLD. The *PNPLA3*-I148M allele was also associated with elevated serum liver enzymes, indicating adverse liver function. The *PNPLA3*-453I allele was independently associated with lower hepatic fat content and did not affect glucose homeostasis or lipoprotein metabolism. These results highlight the role of *PNPLA3* in determining hepatic TG levels and provide insights into the genetic basis of NAFLD.The study investigates genetic variants contributing to differences in hepatic fat content and susceptibility to nonalcoholic fatty liver disease (NAFLD) across different ethnic groups. A genome-wide association scan identified an allele in *PNPLA3* (rs738409; I148M) strongly associated with increased hepatic fat levels and inflammation (P=5.9×10−10 and P=3.7×10−4, respectively). This allele was most prevalent in Hispanics, who have the highest prevalence of NAFLD. Resequencing revealed another allele (*PNPLA3*-S453I) associated with lower hepatic fat content in African-Americans, the group with the lowest risk of NAFLD. These findings suggest that variation in *PNPLA3* contributes to ethnic and individual differences in hepatic fat content and susceptibility to NAFLD. The *PNPLA3*-I148M allele was also associated with elevated serum liver enzymes, indicating adverse liver function. The *PNPLA3*-453I allele was independently associated with lower hepatic fat content and did not affect glucose homeostasis or lipoprotein metabolism. These results highlight the role of *PNPLA3* in determining hepatic TG levels and provide insights into the genetic basis of NAFLD.