The natural history of chronic HCV infection appears to differ depending on the characterstics of the infected population. The progression of the disease can be dramatically affected by many variables including host immunity, virus genotype, viral load, co-infection, alcohol consumption and other environmental factors. The AIM of this study was to determine the natural progression of HCV infection in a special group of blood donors who were infected with HCV at a defined time period as a result of their participation in a plasmaphoresis clinic in rural China. METHODS: 240 blood donors, infected with HCV as a result of participating in repeat plasmaphoresis for 5 years, were first investigated in 1997. None of these patients consumed alcohol. Blood samples from all 240 patients and liver biopsies from 66 patients were obtained in 1997. A second set of liver biopsies were obtained from 85 of those patients in 2010. Pathological analysis was performed in 31 pairs of liver biopsies at an average interval of 13 years. Inflammation and fibrosis were determined by the Metavir system. RESULTS. The majority of patients had genotype 2 or 3 infection. Inflammation grades in 1997 were 25.8% Grade I, 64.5% Grade II, and 9.7% Grade III. In 2010 they were 6.5% Grade I, 74.2% Grade II, and 19.4% Grade III. Fibrosis stage from 1997 was 74.2% Stage I, 22.6% Stage II and 3.22% Stage III. In 2010 they were 22.6% Stage I, 54.8% Stage II, 16.1% Stage III, 6.5% Stage IV. Two patients improved (6.5%), 6 patients (19.5%) remained the same, and 67.7% increased stage over the observation interval. Steatosis was infrequent, 6.5% (2/31). Both fibrosis and inflammation progressed from 1997 to 2010 (P<0.001, Chi-Square Test). Grade scores increased from 2.6± 2.0 to 5.1±2.2. The net increase was 2.5± 2.4 in 13 years and the annual increase was 0.19. Stage Score increased from 1.0± 1.2 to 2.4±1.7. The net increase was 1.5±1. 8 and annual increase was 0.1. The grade increase was related to viral load and ALT in 2010 determined by ONE-WAY ANOVA analysis (P=0.03 and P=0.016 respectively). The increase of fibrosis stage was related to viral load in 1997 and 2010. It was also related to ALT, AST and Bile Acid levels tested in 2010. There was no relationship with age or gender. Of note, two patients with lower viral load in 1997 underwent spontaneous cure, became RNA negative and improved liver histology. CONCLUSIONS: HCV infection in untreated blood donors with no alcohol consumption is progressive but generally shows mild liver injury and slow progression of liver disease. Both viral load and ALT were predictive of progression in this population.