Increased fetuin-A has been reported in association with type 2 diabetes and other metabolic diseases. However, the large population data concerning fetuin-A and nonalcoholic fatty liver disease (NAFLD) were limited. In this study, we aimed to investigate the association of serum fetuin-A with fatty liver index (FLI), the indicator of NAFLD. A population-based cross-sectional analysis was performed in 5219 middle-aged and elderly participants who were recruited from 2 nearby urban communities in Shanghai, China. Serum fetuin-A concentrations were measured by enzyme-linked immunosorbent assay (ELISA). The fourth quartiles of FLI, alanine aminotransferance (ALT), aspartate aminotransferance (AST), and γ-glutamyl transpeptadase (GGT) were defined as elevated FLI, ALT, AST, and GGT, respectively. Fetuin-A was positively associated with log-transformed-FLI, -ALT, -AST, and -GGT after adjustment for the confounding factors (all P < 0.05). Multivariate logistic regression analysis showed that each one-standard deviation increase in serum fetuin-A (120.1 mg/L) was associated with 12% (95% confidence interval [CI] 1.01-1.25, P = 0.04), 13% (95% CI 1.06-1.21, P < 0.001), and 10% (95% CI 1.03-1.17, P = 0.005) increased risk of elevated FLI, ALT, and AST, respectively. Categorical analysis showed that as compared to the lowest quartile, the highest quartile of serum fetuin-A associated with a 35% (95% CI 0.98-1.86), 50% (95% CI 1.24-1.83), and 33% (95% CI 1.10-1.60) increased risk of elevated FLI, ALT, and AST, respectively. No significant association was found with GGT. In Chinese adults, serum fetuin-A concentrations were significantly associated with elevated FLI, ALT, and AST, the early indicators of NAFLD.