Background/PurposeThere are limited studies performing paired liver biopsies in chronic hepatitis C (CHC) patients treated with direct-acting antivirals (DAA). We aimed to investigate the predictors of liver fibrosis changes assessed by paired liver biopsies in these patients. MethodsFrom March 2017 to March 2020, 113 CHC patients were prospectively enrolled to receive DAA therapy at our hospital. Paired liver biopsies were performed at baseline and 12 weeks after the end of treatment. ResultsAmong the entire cohort, the rate of sustained virological response (SVR) was 100%. Four baseline variables independently predicted fibrosis regression, including age <65 years [odds ratio (OR) = 2.725, p = 0.036], fibrosis stages (METAVIR scores) < 3 (OR = 4.874, p = 0.040), hemoglobin levels ≥12.5 g/dL (OR = 3.538, p = 0.029), and platelet counts ≥160 103/μL (OR = 2.958, p = 0.023). Besides, five independent predictors of fibrosis progression included baseline age ≥66 years (OR = 16.351, p = 0.024), body mass index (BMI) ≥26.5 kg/m2 (OR = 21.666, p = 0.009), sofosbuvir/ribavirin use (OR = 29.465, p = 0.031), platelet counts <119 103/μL (OR = 33.739, p = 0.026), and the absence of alanine aminotransferase (ALT) levels declining from >35 U/L at baseline to ≤35 U/L at 4 weeks after baseline (OR = 284.534, p = 0.026). ConclusionFor DAA-treated CHC patients, those with baseline age <65 years, fibrosis stages <3, hemoglobin levels ≥12.5 g/dL, or platelet counts ≥160 103/μL are more likely to attain fibrosis regression. There is a higher risk of fibrosis progression in those with baseline age ≥66 years, BMI ≥26.5 kg/m2, sofosbuvir/ribavirin use, platelet counts <119 103/μL, or the absence of early ALT normalization at 4 weeks after baseline.