The prevalence of hepatitis C virus (HCV) infection in Taiwan was approximately 4% a decade ago, much higher than the worldwide average. This study aimed to assess the HCV burden among 4 million voluntary blood donors after 2 decades of prevention and treatment policies. We retrieved screening results for anti-HCV and HCV RNA from the Database for Evaluating Voluntary Taiwanese Eligible Donors. First-time blood donors who donated blood after 1999 and repeat donors who donated blood more than once between 2013 and 2017 were included to estimate HCV prevalence and incidence, respectively. The Cox proportional hazards model was used to estimate hazard ratios. Geographic variation in HCV prevalence and incidence in 364 townships was also analyzed. The prevalence study included 3,656,598 first-time donors. The overall crude prevalence of anti-HCV decreased from 15.5 to 4.5 per 1,000 donors between 1999 and 2017. Younger birth cohorts had a significantly lower prevalence of anti-HCV. The majority of townships (64.3%) in Taiwan showed a significantly decreased prevalence. The incidence study included 1,393,014 repeat donors followed for 3,436,607 person-years. Ninety-eight donors seroconverted to HCV RNA positivity, resulting in an HCV incidence of 2.9 per 100,000 person-years. Donors living in townships where HCV RNA prevalence was greater than 2 per 1,000 had at least 2.5-fold greater risk of new HCV infection. Conclusion: HCV prevalence in Taiwanese first-time blood donors decreased by 71% in the last 2 decades. However, townships with higher HCV prevalence also showed higher HCV incidence and require more active intervention. (Hepatology Communications 2020;4:1193-1205). C hronic hepatitis C virus (HCV) infection is one of the major etiologies of liver cirrhosis and hepatocellular carcinoma and is also correlated with extrahepatic complications, such as insulin resistance, cryoglobulinemia, and renal disease. (1) The estimated number of viremic infections worldwide is 71.1 million, which accounts for 1% of the world population. (2) Surveys from 10 years ago in Taiwan found that around 4%-5% of the general population was anti-HCV positive (3,4) along with 1.2% of first-time blood donors. (5) Both of these HCV prevalence rates were much higher than the worldwide average. It is therefore important to understand the overall HCV transmission routes in Taiwan and to develop strategies for control. Routine screening for HCV infection among blood donors is essentially active surveillance among