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Patients with non-alcoholic fatty liver disease (NAFLD) and significant fibrosis (fibrosis stage ≥2) are candidates for pharmacological trials. The aim of this study was to perform a head-to-head comparison of the diagnostic test characteristics of three non-invasive stiffness-based models including MEFIB (magnetic resonance elastography [MRE] plus FIB-4), MAST (magnetic resonance imaging [MRI]-aspartate aminotransferase [AST]), and FAST (FibroScan-AST) for detecting significant fibrosis. This prospective study included 563 patients with biopsy-proven NAFLD undergoing contemporaneous MRE, MRI proton density fat fraction (MRI-PDFF) and FibroScan from two prospective cohorts derived from Southern California and Japan. Diagnostic performances of models were evaluated by area under the receiver-operating characteristic curve (AUC). The mean age of the cohort was 56.5 years (51% were women). Significant fibrosis was observed in 51.2%. To detect significant fibrosis, MEFIB outperformed both MAST and FAST (both p <0.001); AUCs for MEFIB, MAST, and FAST were 0.901 (95% CI 0.875–0.928), 0.770 (95% CI 0.730–0.810), and 0.725 (95% CI 0.683–0.767), respectively. Using rule-in criteria, the positive predictive value of MEFIB (95.3%) was significantly higher than that of FAST (83.5%, p = 0.001) and numerically but not statistically greater than that of MAST (90.0%, p = 0.056). Notably, MEFIB's rule-in criteria covered more of the study population than MAST (34.1% vs. 26.6%; p = 0.006). Using rule-out criteria, the negative predictive value of MEFIB (90.1%) was significantly higher than that of either MAST (69.6%) or FAST (71.8%) (both p < 0.001). Furthermore, to diagnose "at risk" non-alcoholic steatohepatitis defined as NAFLD activity score ≥4 and fibrosis stage ≥2, MEFIB outperformed both MAST and FAST (both p < 0.05); AUCs for MEFIB, MAST, and FAST were 0.768 (95% CI 0.728–0.808), 0.719 (95% CI 0.671–0.766), and 0.687 (95% CI 0.640–0.733), respectively. MEFIB was better than MAST and FAST for detection of significant fibrosis as well as "at risk" NASH. All three models provide utility for the risk stratification of NAFLD. Non-alcoholic fatty liver disease (NAFLD) affects over 25% of the general population worldwide and is one of the main causes of chronic liver disease. Because so many individuals have NAFLD, it is not practical to perform liver biopsies to identify those with more severe disease who may require pharmacological interventions. Therefore, accurate non-invasive tests are crucial. Herein, we compared three such tests and found that a test called MEFIB was the best at detecting patients who might require treatment. [Display omitted] • Patients with NAFLD and significant fibrosis (fibrosis stage ≥2) are candidates for pharmacological trials. • We performed a head-to-head comparison of the diagnostic test characteristics of three non-invasive stiffness-based models. • To detect significant fibrosis, MEFIB outperformed both MAST and FAST (both p <0.001). • MEFIB demonstrated a robust PPV (95%) and NPV (90%), and should be used in a two-step strategy to identify significant fibrosis. [ABSTRACT FROM AUTHOR]