Abstract: Objective To establish a diagnosis model combining four serum markers of hepatic fibrosis (HA, LN, PⅢNP, CⅣ) and assess the diagnostic performance of model aimed to discriminate between patients with and without significant hepatic fibrosis in patients with hepatitis B. Methods Total of 485 patients with hepatitis B were randomly divided into an estimation group (324 cases) and a validation group (161 cases). The serum levels of HA, LN, PⅢNP and CⅣ were measured by radiommunoassay in all patients and liver biopsy was used as the gold standard. A binary logistic regression model was established combining four serum markers and applied to the validation group to test its accuracy. The diagnostic value of the model was assessed by the receiver operating characteristic (ROC) curves. Results Binary logistic regression identified HA, PⅢNP and CⅣ as independent predictors of fibrosis. We constructed a model named FSM combining HA, PⅢNP and CⅣ that proved useful to identify patients with or without significant hepatic fibrosis in patients with hepatitis B. FSM = 1.56 × ln (HA) ＋ 0.92 × ln (PⅢNP) ＋ 1.9 × ln (CⅣ) － 8.18. The area under the ROC curve (AUC) was 0.85 for predicting significant fibrosis. In validation group, the AUC was also 0.85 for predicting significant fibrosis. Using optimized cutoff values, the sensitivity and negative predictive value of predicting the absence of significant fibrosis (FSM ＜ 10.8) were 88.31% and 69%, while the specificity and positive predictive value of predicting the presence of significant fibrosis (FSM ≥ 12.6) were 93.55% and 95.3%. Comparing the FSM diagnostic model and HA, the Youden’s index, positive likelihood ratio, sensitivity, specificity and accuracy of FSM model were higher than those of HA, and AUC had significant difference between the two (Z = 2.06, P ＜ 0.05). Conclusions The FSM model established in this study improved the diagnostic performance. It can make the 65%-70% patients without significant hepatic fibrosis to avoid “liver biopsy”. As a noninvasive method, it can be employed for monitoring the progression of hepatic fibrosis.