Fetuin-A is a hepatic secretory protein and a novel risk factor for diabetes. However, it remains unclear whether the association between high levels of fetuin-A and diabetes can be attributed to nonalcoholic fatty liver disease. We conducted a case-cohort study among 1,957 subcohort members and 455 incident diabetes cases in the Multi-Ethnic Study of Atherosclerosis, a multicenter US study of Caucasian, African-American, Hispanic, and Chinese-American adults aged 45-84 years. Serum fetuin-A and computed tomography-determined liver fat content were measured from samples collected at baseline (2000-2002). In multivariable Cox proportional hazards models with follow-up through 2012, a higher fetuin-A level was associated with a higher risk of diabetes, with a stronger association among women (for top quartile vs. bottom, hazard ratio (HR) = 3.36, 95% confidence interval (CI): 2.08, 5.44) than among men (HR = 1.47, 95% CI: 0.93, 2.35) (P-heterogeneity = 0.001). Adjustment for liver fat content attenuated these associations slightly (women: HR = 2.61, 95% CI: 1.59, 4.26; men: HR = 1.32, 95% CI: 0.84, 2.08). In this study, we observed a particularly strong association of fetuin-A with diabetes risk in women that could not be explained by liver fat.