A fatty liver, which is a common feature in insulin-resistant states, can lead to chronic liver disease. It has been hypothesized that a fatty liver can also increase the rates of non-hepaticrelated morbidity and mortality. Therefore, we wanted to determine whether the fatty liver index (FLI), a surrogate marker and a validated algorithm derived from the serum triglyceride level, body mass index, waist circumference, and c-glutamyltransferase level, was associated with the prognosis in a population study. The 15-year all-cause, hepatic-related, cardiovascular disease (CVD), and cancer mortality rates were obtained through the Regional Health Registry in 2011 for 2074 Caucasian middle-aged individuals in the Cremona study, a population study examining the prevalence of diabetes mellitus in Italy. During the 15-year observation period, 495 deaths were registered: 34 were hepatic-related, 221 were CVD-related, 180 were cancer-related, and 60 were attributed to other causes. FLI was independently associated with the hepatic-related deaths (hazard ratio 5 1.04, 95% confidence interval 5 1.02-1.05, P < 0.0001). Age, sex, FLI, cigarette smoking, and diabetes were independently associated with all-cause mortality. Age, sex, FLI, systolic blood pressure, and fibrinogen were independently associated with CVD mortality; meanwhile, age, sex, FLI, and smoking were independently associated with cancer mortality. FLI correlated with the homeostasis model assessment of insulin resistance (HOMA-IR), a surrogate marker of insulin resistance (Spearman's q 5 0.57, P < 0.0001), and when HOMA-IR was included in the multivariate analyses, FLI retained its association with hepatic-related mortality but not with all-cause, CVD, and cancer-related mortality. Conclusion: FLI is independently associated with hepatic-related mortality. It is also associated with all-cause, CVD, and cancer mortality rates, but these associations appear to be tightly interconnected with the risk conferred by the correlated insulin-resistant state. (HEPATOLOGY 2011;54:145-152) See Editorial on Page 6 N onalcoholic fatty liver disease (NAFLD) is common in insulin-resistant subjects 1 and affects 20% to 30% of the adult population and more than 50% of overweight and obese individuals. 2 NAFLD is associated with an increased risk of developing advanced fibrosis and cirrhosis 3 and incident type 2 diabetes. 4 Because of its association with metabolic syndrome and type 2 diabetes, it has been hypothesized that NAFLD may also be associated with increased rates of cardiovascular disease (CVD) 5 ; in particular, patients with NAFLD have elevated levels of plasma biomarkers of Abbreviations: BMI, body mass index; CI, confidence interval; CVD, cardiovascular disease; FLI, fatty liver index; GGT, c-glutamyltransferase; HOMA-IR, homeostasis model assessment of insulin resistance; HR, hazard ratio; IGT, impaired glucose tolerance; NAFLD, nonalcoholic fatty liver disease; OGTT, oral glucose tolerance test.