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Background: Despite screening blood donations with advanced technologies and improved donor screening, the risk of transfusion-transmitted infections persists. This risk is mainly due to blood donations collected during the window period. A precise estimate of the transfusion risk of viral infection will help to determine the effect of new and current safety measures and to prioritize and allocate limited resources. Therefore, we estimated the risk of transfusion-transmitted viral infection in blood donations collected in Korea from 2000 to 2010. Methods: Blood donations collected at 16 blood centers were tested for HIV, HCV, and HBV to estimate the residual risk of transfusion-transmitted viral infection. The residual risk was calculated in two-year periods using the incidence/window model. The incidence rates for HIV/HCV and the confirmed positive rate for HIV/HCV in first-time and repeat donors were compared. Results: The residual risks for HIV in 2004/2005 and 2009/2010 were 1 in 1,080,244 and 1 in 1,356,547, respectively. The risks for HCV in 2000/2001 and 2009/2010 were 1 in 81,431 and 1 in 2,984,415, and the risks for HBV in 2000/2001 and 2009/2010 were 1 in 45,891 and 1 in 43,666. These estimates indicate that the residual risks for HCV in Korea have declined 36.6-fold, and those for HIV and HBV have not improved significantly, compared to previous estimates. The odds ratios for HCV and HBV positivity in first-time donors compared to repeat donors were 11.8 and 19.6, respectively. Conclusions: The residual risk of HCV declined over the last decade due to improved screening reagents, implementation of the nucleic acid amplification test, and tight application of strict donor selection procedures. Current residual risk estimates for HIV and HCV in Korea are extremely low, but the risk for HBV is still high; therefore, urgent measures should focus on decreasing the residual risk of HBV. Despite the introduction of more sensitive assays in blood screening, several other factors may influence the actual residual risk of transfusion-transmitted infection. A continuous monitoring of residual risk of transfusion-transmitted infection is crucial in managing blood safety. [ABSTRACT FROM AUTHOR]