AIM: To determine factors associated with fibrosis progression in hepatitis C virus (HCV)-infected patients without significant initial pathological lesions.METHODS: Seventy six untreated HCV-infected patients with initially normal liver as defined by a Knedell score ≤ 3,with 2 liver biopsies and detectable HCVRNA were included.Markers of fibrosis progression were assessed.RESULTS: Median duration of infection and time between paired biopsies was 13 (95% CI: 1-28)and 4 (95% CI: 2-16) years respectively.Alaninetransaminase (ALT) activity was normal in 43.4% of cases.50% demonstrated progression of the necroinflammation and 34% of fibrosis after a median time evolution of 4 years (95% CI: 2-16).The median difference in the necro-inflammation and fibrosis score between biopsies was low,1.5 and 0.0 respectively.Univariate analysis showed there was no difference between fibrosis activity or evolution according to genotype or viral load.A higher fibrosis progression (P = 0.03) was observed in patients with body mass index (BMI) ＞25.Fibrosis progression correlated with the time interval between biopsies (P = 0.01).A significant progression of activity (1.7 vs 0.4,P＜0.05) or fibrosis (0.9 vs 0.0,P ＜ 0.01) was observed in patients with elevated ALT.There was a significant correlation between activity progression and fibrosis progression(P = 0.003).Multivariate analysis demonstrated that fibrosis progression was associated with elevated ALT,BMI＞25 and the time interval between 2 biopsies.CONCLUSION: There is no fibrosis progression in 66% of patients without significant initial histopathological lesion.Fibrosis progression is associated with elevated ALT and BMI ＞ 25.