OBJECTIVE: The INTERCEPT Blood System (IBS) for platelets has been developed to reduce pathogen transmission risks during platelet transfusions. This study assessed the cost-effectiveness of using single-donor platelets (SDP) and random-donor platelets (RDP) processed with a pathogen inactivation treatment (SDP+IBS and RDP+IBS) during orthopedic surgery, which accounts for approximately 10% of platelets usage in the U.S. METHODS: A decision-analytic model was developed to simulate the possible transfusion-related events and outcomes in three reference patients: a female aged 60, 70, or 80 years, and undergoing a total hip arthroplasty. Avoidance of pathogen exposure to HIV, HCV, HBV, HTLV-I, and transfusion-related sepsis(TRS) was incorporated in the model. Clinical outcomes were measured by quality adjusted life-year gained (QALYs). The direct medical costs of IBS and transfusion-related complications were incorporated in the baseline model. No indirect costs (e.g., work productivity losses) or transfer costs (litigation) were considered. Possible benefit on reducing emerging pathogens risk was explored by incorporating a hypothetical HCV-like pathogen into sensitivity analyses. RESULTS: The incremental cost per QALY gained of using SDP+IBS vs. untreated SDPs, ranged from $1,686,000 (at age 60)-$3,362,000 (at age 80). Corresponding figures for RDP+IBS vs. RDPs, ranged from $642,000-$1,404,000. Inclusion of an emerging pathogen benefit significantly improved the cost effectiveness to $423,000-$1,304,000 for SDP and $66,000-$237,000 for RDP. Sensitivity analysis showed that results were most sensitive to reductions in platelet yield and case fatality rate from bacteria contamination, but less sensitive to viral transmission risks. CONCLUSIONS: The cost-effectiveness of IBS in orthopedic surgery patients appears to be comparable to that of other widely accepted blood safety interventions(e.g. NAT testing). Therefore, pathogen inactivation with the IBS for platelets should be considered to be a relatively cost-effective strategy to improve the safety of platelet transfusions and a potential insurance against the threat of emerging pathogens.