BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) can trigger inflammation, hepatocellular damage, cirrhosis, and hepatocellular carcinoma. There is a need for non-invasive, cost-effective diagnostic markers for MAFLD, as current methods like liver biopsy are invasive. This study investigates the potential of the systemic immune inflammation index (SII) as a useful tool in diagnosis of MAFLD. METHODS: A cohort of 806 individuals, including 426 with MAFLD and 380 controls, was analyzed. SII values, along with various biochemical and inflammatory markers, were compared between groups. RESULTS: The MAFLD group exhibited significantly higher SII values, which correlated with key markers of liver inflammation and function. Median SII levels of the MAFLD patients (581 (45-4553)) were significantly higher than that of the control group (423 (112-2595)) ( CONCLUSIONS: These findings suggest that SII could serve as a useful, noninvasive marker for diagnosing and monitoring MAFLD, warranting further longitudinal studies to explore its role in disease progression and treatment response.