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Currently, there is no consistent information on the course of fibrosis-4 (FIB-4) score changes in non-alcoholic fatty liver disease (NAFLD) or their association with subsequent risk of cirrhosis and/or hepatocellular carcinoma (HCC). Thus, we aimed to evaluate the association between longitudinal changes in FIB-4 and subsequent risk of HCC and a composite endpoint of cirrhosis and HCC in patients with NAFLD. We conducted a retrospective cohort study of patients with NAFLD seen in 130 Veterans Administration hospitals between 1/1/2004-12/31/2008, with follow-up through to 12/31/2018. We calculated FIB-4 longitudinally and categorized patients based on risk of advanced fibrosis (low-risk FIB-4 <1.45, indeterminate-risk FIB-4 1.45-2.67, and high-risk FIB-4 >2.67). We used landmark Fine-Gray competing risks models to determine the effects of change in FIB-4 between NAFLD diagnosis date and 3-year landmark time on the subsequent risk of HCC and a composite endpoint. Among the 202,319 patients with NAFLD in the 3-year landmark analysis, 473 progressed to HCC at an incidence rate of 0.28 per 1,000 person years (PY) (95% CI 0.26–0.30). The incidence rate of the composite endpoint was 1.31 per 1,000 PY (95% CI 1.25–1.37). At baseline, 74.7%, 21.4%, and 3.8% of patients had a low, indeterminate, and high FIB-4, respectively. Compared to patients who were at stable low FIB-4 at both time points, the risk of HCC and that of the composite endpoint was higher for all other subgroups with the highest risk in patients with persistently high FIB-4 (HCC adjusted sub-distribution hazard ratio 57.7, 95% CI 40.5–82.2 and composite endpoint hazard ratio 28.6, 95% CI 24.6–33.2). Longitudinal changes in FIB-4 were strongly associated with progression to cirrhosis and HCC. Tools to stratify the risk of HCC development in patients with NAFLD are currently lacking. The fibrosis-4 (FIB-4) score is a widely available non-invasive test for liver fibrosis, a primary determinant of the development of cirrhosis and HCC. In a large retrospective cohort of patients with NAFLD, we found that serial changes in FIB-4 over time were strongly associated with progression to cirrhosis and HCC. Integrating serial measurements of non-invasive tests for fibrosis into the care pathway for patients with NAFLD could help tailor HCC risk prevention. [Display omitted] • An increase in FIB-4 value over time was associated with risk of developing cirrhosis and HCC in patients with NAFLD. • High FIB-4 (>2.67) at baseline and 3 years linked to a >50-fold higher risk of HCC than persistently low FIB-4 (<1.45) values. • 75% of patients were at low, 21% indeterminate (1.45-2.67) and 4% high risk of advanced fibrosis based on baseline FIB-4 value. • More than 50% of patients with NAFLD remained within the same FIB-4 risk group after 3 years. • Repeating FIB-4 measurements in clinical practice was strongly associated with progression to cirrhosis and HCC. [ABSTRACT FROM AUTHOR]