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Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related fatality reported to the Food and Drug Administration. Donor screening may reduce TRALI risk. This study sought to compare the efficacy and safety of different TRALI risk-reduction strategies at a hospital-based donor center.Samples from 1053 donors who answered questions regarding pregnancy and transfusion history were tested for HLA Class I and II antibodies using a flow cytometry–based screening assay. Donor history was compared with the presence of HLA alloantibodies. These data were used to model several TRALI risk-reduction strategies. The medical records of patients transfused fresh-frozen plasma (FFP) from highly alloimmunized donors were retrospectively reviewed for TRALI.HLA alloimmunization was observed among 25.4 percent (256/1009) of all female donors and among 12.0 percent (3/25) of those male donors who gave a history of prior transfusion. Prior pregnancy, reported by 52.6 percent (531/1009) of females, correlated significantly with HLA alloimmunization (p < 0.0001). The rate of HLA alloimmunization increased with parity. A positive pregnancy history was a sensitive (87.9%) screen for HLA alloimmunization with a negative predictive value of 93.5 percent (95% confidence interval, 91.3%-95.7%). Although 5.9 percent (27/459) of nulliparous, untransfused females demonstrated a positive screening test, only 1 percent (7/459) had a confirmed HLA alloantibody. Transfusion of FFP from donors found retrospectively to be highly alloimmunized led to reactions suggestive of TRALI in 2 of 26 recipients.Donor history is a reliable predictor of HLA alloimmunization. Testing only donors with a prior history of pregnancy or transfusion is a logical and cost-effective TRALI prevention strategy.