Objective Understanding the natural history of chronic hepatitis C (CHC) may assist clinical decision-making and prompt medical intervention to decrease the development of complications.It has been suggested that different modes of HCV transmission affect the natural history of chronic hepatitis C (CHC) patients.Paid plasma donation was an important route of blood-borne HCV infection before the early 1990s worldwide.The fibrosis progression confirmed by histopathological analysis for plasma donors with CHC are largely unknown.The purpose of this study was to evaluate the fibrosis progression and explore its influence factors in interferon treatment-naive Chinese plasma donors with chronic hepatitis C infected 20 years.Methods A cohort of 122 interferon-treatment-naive CHC infected by plasma donation between 1992 to 1995 was investigated.These donors were infected by HCV through sharing contaminated,recycled equipment during the donation process.From 2010 to 2011,clinical data including demography,liver function,sera HCV RNA level,and HCV genotype,etc were collected.Among these enrolled patients,one hundred and twenty patients underwent liver biopsy,and their liver fibrosis stage was evaluated by Metavir scoring,liver inflammation was evaluated by Scheuer scoring system,hepatic steatosis was graded based on the proportion of hepatocytes with fat.For the other 2 patients,one case of cirrhosis did not receive liver biopsy due to ascites;another patient was excluded because ofthe small size of specimen of liver biepsy tissue unsuitable for pathological test.Results Cirrhosis was observed in 2.5% (3/121)patients (F4 was found in two patients by biopsy,one cirrhosis patient with ascites confirmed by physical examination and Doppler ultrasound).F1 and F2 were present in 45.5% (55/121) and 41.3% (50/121) of patients,respectively.Patients with older age,higher sera HCV RNA load (≥ 4log10),elevated alanine aminotransferase (≥40U/L),and liver necroinflammation (≥G2) showed significant association with higher fibrosis degree (all P<0.05).The severity of liver inflammation was an independently related to the moderate-severe fibrosis (≥ F2) (odd ratio=5.02,P<0.05)..Conclusion Based on liver histopathological analysis,in our Chinese cohort of CHC plasma donors without interferon therapy,86% of patients presented with stage F1 and F2 fibrosis after HCV infection for ~20 years.Liver inflammation is closely related to the development of moderate-severe liver fibrosis,so prompt control of liver inflammation may postpone the progression of cirrhosis.