Abstract: Background and Objective: As liver biopsy had multiple procedure-related complications, the introduction of reliable noninvasive tests for accurate discrimination of NASH and liver fibrosis in patients with NAFLD are mandatory. The aim was to elucidate the diagnostic value of fibrosis-4 index (FIB-4), Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) and Cytokeratin-18 fragments (CK18-Fs) in the prediction of NASH and liver fibrosis. Materials and Methods: One hundred Egyptian patients with NAFLD selected from outpatient's clinics of Mansoura University Hospitals underwent histological examination through liver biopsy after approval and consent. The FIB-4, HOMA-IR, CK18-Fs (measured using a human ELISA Kit) and their combination in FICK-3 score were investigated for predicting NASH and liver fibrosis. Receiver operating characteristic (ROC) curves and multivariate logistic regression were analyzed. Results: In patients with NAFLD, the areas under the ROC were significantly high (AUC: 0.765, 0.700, 0.803, 0.835 for FIB-4, HOMA-IR, CK18-Fs, FICK-3 score, respectively, p = 0.05) displaying a highly statistically significant predictive ability for NASH. Significantly higher AUCs for these parameters were demonstrated predicting early-or advanced-stage liver fibrosis (AUC >0.7, p<0.01). Also, the combined FICK-3 score (the sum of FIB-4 >1.46, HOMA-IR >2.11 and CK18-Fs >307U L–1) had highly significant predictive values for NASH and liver fibrosis and had the best diagnostic accuracy at a cutoff value of 1(AUC >0.8, p<0.001). Contrasted with other diagnostic scores, FICK-3 had the best diagnostic accuracy for detection of fibrotic NASH (AUC = 0.954, p<0.001) and positively correlated with the histological features of NAFLD. Conclusion: The new combination FICK-3 score was a reliable and significant predictor for NASH and liver fibrosis in NAFLD Egyptian patients.