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Objective: Metabolic dysfunction–associated steatotic liver disease (MASLD; formerly termed nonalcoholic fatty liver disease [NAFLD]) is a leading cause of chronic liver disease and related morbidity. Orlistat, a lipase inhibitor that reduces fat absorption, is used for weight loss. This study aimed to evaluate the association between orlistat use and changes in the Fatty Liver Index (FLI). Methods: This study included 54 patients with a body mass index (BMI) >30 kg/m² who applied to the Obesity Center of the University of Health Sciences Gazi Yaşargil Training and Research Hospital between January 2019 and January 2024, and had used orlistat continuously for at least 3 months. Anthropometric measurements and laboratory results recorded in the Hospital Information System (HIS) were extracted at baseline (Month 0; index visit), and at Months 3 and 6 during orlistat use, and FLI was calculated at each time point. Results: A total of 54 patients were included in the study, comprising 52 females and 2 males. The mean baseline body weight of the participants was 103.87 ± 13.01 kg. Following regular orlistat use, significant reductions were observed in several clinical and biochemical parameters, including the FLI, BMI, waist circumference, gammaglutamyl transferase (GGT), alanine aminotransferase (ALT), fasting blood glucose, and body weight (p-values: <0.001, <0.001, <0.001, 0.002, 0.002, 0.046, and <0.001, respectively). In contrast, changes in triglyceride and aspartate aminotransferase (AST) levels were not statistically significant (p = 0.225 and p = 0.154, respectively). Conclusion: In this retrospective study, orlistat use was associated with a significant reduction in FLI, accompanied by decreases in body weight, waist circumference, and liver enzyme levels. These findings support its potential role in the management of obesity related fatty liver disease.