Aim: Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in patients with obesity and type 2 diabetes mellitus (T2DM), and has been associated with the single nucleotide polymorphism (SNP) rs738409 in the PNPLA3 gene. This association remains to be investigated in African Americans with T2DM, a group at lower risk for hepatic steatosis relative to European Americans with T2DM. Methods: We examined 422 African Americans with T2DM (40.3% male; age: 56.4 ± 9.6 years; Body Mass Index: 35.2 ± 8.2 kg/m2), all with measures of liver density reflecting hepatic fat content on abdominal computed tomography, and blood glucose and lipid profiles. Associations between rs738409 and phenotypes of interest were determined using SOLAR, assuming an additive model of inheritance with covariates age, sex, BMI and use of lipid-lowering medications. Results: Mean ± SD liver density was 55.4 ± 10.2 Hounsfield Units. SNP rs738409 in PNPLA3 was significantly associated with liver density (P = 0.0075) and hepatic steatosis (P = 0.0350), but not with blood glucose, HbA1c, total cholesterol, triglycerides, high-density or low-density lipoprotein levels or liver function tests (P = 0.15–0.96). Conclusion: These findings provide evidence that the PNPLA3 SNP rs738409 contributes to risk for increased liver fat content in African Americans with T2DM, an effect that appears to be independent from serum lipids. Although African Americans are less susceptible to fatty liver than European Americans, PNPLA3 appears to be a risk locus for hepatic steatosis in diabetic African Americans.