<p>While metabolic dysfunction-associated fatty liver disease (MAFLD) includes the homeostatic model assessment for insulin resistance (HOMA-IR) as one of the criteria to define metabolic dysregulation, the newly proposed metabolic dysfunction-associated steatotic liver disease (MASLD) has removed this criterion. We investigated whether the HOMA-IR can serve as an independent predictive marker for significant fibrosis in subjects with MAFLD. This is a cross-sectional multicenter study. We enrolled a total of 364 patients diagnosed with MAFLD. We conducted a multiple logistic regression analysis to assess the relationship between HOMA-IR and advanced stages of liver fibrosis (F ≥ 2), as assessed by the FIB-4 score and liver stiffness measurement (LSM). Each unit increase in insulin resistance, as measured by HOMA-IR, was associated with a 16% higher likelihood of displaying significant fibrosis, as determined by a non-invasive scoring test, regardless of diabetes or BMI status. HOMA-IR was independently associated with significant fibrosis in non-diabetic (OR: 1.14, 95% CI: 1.07–1.21, P &lt; 0.001) and diabetic (OR: 1.03, 95% CI: 1.00–1.06, P = 0.03) patients. Moreover, significant fibrosis in lean was independently linked to HOMA-IR (OR: 1.06, 95% CI: 1.01–1.12, P = 0.03) and non-lean (OR: 1.04, 95% CI: 1.02–1.07, P &lt; 0.001) patients. Insulin resistance measured by HOMA-IR should be assessed in patients with MAFLD as a key factor of disease progression and incorporated into the disease diagnostic criteria.</p>