Background and Objectives: The risk of transfusion-transmitted hepatitis C virus (HCV) infections is extremely low in Australia. This study aims to conduct a cost-effectiveness analysis of different testing strategies for HCV infection in blood donations. Materials and Methods: The four testing strategies evaluated in this study were universal testing with both HCV antibody (anti-HCV) and nucleic acid testing (NAT); anti-HCV and NAT for first-time donations and NAT only for repeat donations; anti-HCV and NAT for transfusible component donations and NAT only for plasma for further manufacture; and universal testing with NAT only. A decision-analytical model was developed to assess the cost-effectiveness of alternative HCV testing strategies. Sensitivity analysis and threshold analysis were conducted to account for data uncertainty. Results: The number of potential transfusion-transmitted cases of acute hepatitis C and chronic hepatitis C was approximately zero in all four strategies. Universal testing with NAT only was the most cost-effective strategy due to the lowest testing cost. The threshold analysis showed that for the current practice to be cost-effective, the residual risks of other testing strategies would have to be at least 1 HCV infection in 2424 donations, which is over 60,000 times the baseline residual risk (1 in 151 million donations). Conclusion: The screening strategy for HCV in blood donations currently implemented in Australia is not cost-effective compared with targeted testing or universal testing with NAT only. Partial or total removal of anti-HCV testing would bring significant cost savings without compromising blood recipient safety.