Objectives: We aimed to evaluate the cost-effectiveness of offering once-off birth cohort testing for hepatitis C virus (HCV) to people in Ireland born between 1965 and 1985, the cohort with the highest reported prevalence of undiagnosed chronic HCV infection.Methods: Systematic and opportunistic HCV birth cohort testing programs, implemented over a 4-year timeframe, were compared with the current practice of population risk-based testing only in a closed-cohort decision tree and Markov model hybrid over a lifetime time horizon. Outcomes were expressed in quality-adjusted life-years (QALYs). Costs were presented from the health system's perspective in 2020 euro ( euro ). Uncertainty was assessed via deterministic, probabilistic, scenario, and threshold analyses.Results: In the base case, systematic testing yielded the largest cost and health benefits, followed by opportunistic testing and risk-based testing. Compared with risk-based testing, the incremental cost-effectiveness ratio for opportunistic testing was euro 14 586 (95% confidence interval euro 4185- euro 33 527) per QALY gained. Compared with opportunistic testing, the incremental cost-effectiveness ratio for systematic testing was euro 16 827 (95% confidence interval euro 5106- euro 38 843) per QALY gained. These findings were robust across a range of sensitivity analyses.Conclusions: Both systematic and opportunistic birth cohort testing would be considered an efficient use of resources, but systematic testing was the optimal strategy at willingness-to-pay threshold values typically used in Ireland. Although cost-effective, any decision to introduce birth cohort testing for HCV (in Ireland or elsewhere) must be balanced with considerations regarding the feasibility and budget impact of implementing a national testing program given high initial costs and resource use.