The impact of circulating microRNA-122 (miR-122) on mortality in patients with histopathologically confirmed nonalcoholic fatty liver disease (NAFLD) remains unclear. We analyzed the overall survival rates in 441 Japanese patients with histopathologically confirmed NAFLD after a median follow-up period of 4.7 years. We also determined the clinicopathologic, genetic, and epigenetic parameters, including serum miR-122 levels, for prediction of mortality. Of the 441 study patients, 21 (4.8%) died during the follow-up period. The cumulative survival rates were 95.4% and 90.6% at the end of 5 and 10 years, respectively. Multivariate analysis identified history of liver cancer (presence; hazard ratio [HR], 4.94; 95% confidence interval [CI], 1.84-13.3), serum miR-122 (<1.00 fold change; HR, 4.35; 95% CI, 0.06-0.83), and fibrosis-4 index (FIB-4 index) (≥1.30; HR, 15.7; 95% CI, 2.01-122) as significant risk factors of mortality. Cumulative survival rates varied significantly among patients with none/one risk factor, two risk factors, and three risk factors; particularly, the survival rate of patients with three risk factors was significantly lower than those with two risk factors and none/one risk factor. Two or more risk factors were identified in 17 of 21 (81.0%) death cases. Conclusion: The importance of serum miR-122 and FIB-4 index as risk factors for mortality in Japanese patients with histopathologically confirmed NAFLD is shown. Early diagnosis based on the presence of more than one risk factor and early treatment might improve the prognosis. (Hepatology Communications 2020;4:66-76).