Background Allergic transfusion reactions (ATRs) are among the most common complications of transfusion. Storage in platelet additive solution (PAS) has been shown to reduce ATRs from apheresis platelets (APs). This study evaluated the cost-effectiveness of using PAS storage as an alternative method to reduce ATRs. Study Design and Methods A Markov-based decision tree was constructed to compare ATR rates and associated costs expected from current practice and from alternative strategies of using APs stored in PAS. The potential use of pretransfusion medication was also incorporated. Using a hospital perspective and including direct medical expenses only (US$2012), Monte Carlo microsimulations were run to evaluate outcomes under a base-case analysis. One-way and probabilistic sensitivity analyses were used to assess outcome uncertainty. Results Under base-case variables, using APs stored in PAS for all patients as an initial transfusion protocol is expected to avert ATRs and associated costs, compared to current practice. Using PAS for all patients along with pretransfusion medication would be cost-saving only when the additional cost of PAS is below $9.14. If PAS storage could eliminate pretransfusion medication use, it is expected to result in cost savings when the additional unit cost of PAS is under $11.90. At a PAS cost of $15, averting one ATR would cost $701.95. Using PAS storage only in response to recurring mild ATRs is associated with cost savings under all costs of PAS evaluated. Conclusions Using PAS storage for all AP transfusions to prevent ATRs may be financially and clinically beneficial, compared to current practice.