BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) spectrum ranges from simple hepatic steatosis to non-alcoholic steatohepatitis. Considering the restrictions of liver biopsy, various serological biomarkers have recently emerged for non-invasive diagnosis of NAFLD. AIM: This study aimed to evaluate the association between serum neuregulin 4 (Nrg4) and NAFLD and the use of serum Nrg4 as a noninvasive marker for diagnosis of NAFLD. METHODS: Sixty-three Egyptian NAFLD patients and 63 controls were enrolled and subjected to detailed history taking, thorough clinical examination including anthropometric measures (body mass index [BMI] and waist circumference). Laboratory investigations included complete blood count, lipid profile (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein-cholesterol [HDL-C], triglycerides), serum albumin, transaminases, bilirubin levels, hepatitis markers (anti-HCV antibodies and hepatitis B surface antigen), anti-nuclear antibodies and anti-smooth muscle antibody. Measurement of serum Nrg4 by ELISA and non-invasive NAFLD scores such as NAFLD fibrosis score and FIB4 score were applied to all patients. RESULTS: There was a statistically significant difference between cases and controls regarding the BMI, waist circumference, hemoglobin level, total leukocytic count, total cholesterol, LDL-C, HDL-C, and serum triglycerides levels. Nrg4 was significantly decreased in NAFLD patients as compared to controls. Moreover, Nrg4, total cholesterol, and LDL-C levels were statistically significant independent predictors of NAFLD. No significant differences were observed between Nrg4 level and the variable stages of hepatic fibrosis by NAFLD fibrosis score. CONCLUSION: Decreased serum Nrg4 level is frequent in NAFLD patients and is an independent predictor of NAFLD, suggesting that Nrg4 might have a potential role in prevention and treatment of NAFLD.