Current guidelines recommend a two-step approach for risk stratification in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) involving Fibrosis-4 index (FIB-4) followed by liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) or similar second-line tests. This study aimed to examine the prognostic performance of this approach.The VCTE-Prognosis study was a longitudinal study of patients with MASLD who had undergone VCTE examinations at 16 centres from the US, Europe and Asia with subsequent follow-up for clinical events. The primary endpoint was incident liver-related events (LREs), defined as hepatic decompensation and/or hepatocellular carcinoma.Of 12,950 patients (mean age 52 years, 41% female, 12.1% LSM >12 kPa), baseline FIB-4, at cut-offs of 1.3 (or 2.0 for age ≥65) and 2.67, classified 66.3% as low-risk and 9.8% as high-risk, leaving 23.9% in the intermediate-risk zone. After classifying intermediate FIB-4 patients as low-risk if LSM was 12.0 kPa, 81.5%, 4.6%, and 13.9% of the full cohort were classified as low-, intermediate-, and high-risk, respectively. At a median (IQR) follow-up of 47 (23-72) months, 248 (1.9%) patients developed LREs. The 5-year cumulative incidence of LREs was 0.5%, 1.0% and 10.8% in the low-, intermediate- and high-risk groups, respectively. Replacing LSM with Agile 3+, Agile 4, and FAST did not reduce the intermediate-risk zone or improve event prediction. Classifying intermediate FIB-4 patients by LSM 15 kPa (high-risk) reduced the intermediate-risk zone while maintaining predictive performance.The non-invasive two-step approach of FIB-4 followed by LSM is effective in classifying patients at different risks of LREs.Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as one of the leading causes of cirrhosis and hepatocellular carcinoma worldwide, but only a minority of patients will develop these complications. Therefore, it is necessary to use non-invasive tests instead of liver biopsy for risk stratification. Additionally, as most patients with MASLD are seen in primary care instead of specialist settings, cost and availability of the tests should be taken into consideration. In this multicentre study, the use of the Fibrosis-4 index followed by liver stiffness measurement by vibration-controlled transient elastography effectively identified patients who would later develop liver-related events. The results support current recommendations by various regional guidelines on a clinical care pathway based on non-invasive tests to diagnose advanced liver fibrosis.