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Background Leukoreduction prior to packed red blood cell (pRBC) storage is not a universally accepted practice. Our laboratory has previously shown that microvesicles (MVs) accumulate in pRBC units during storage and play an important role in lung injury after resuscitation. Currently, the effect of leukoreduction on MV formation in stored pRBC units is unknown. In the present study, we investigated the hypothesis that leukoreduction of pRBC units prior to storage would attenuate the production of MVs and decrease pulmonary inflammation after hemorrhage and resuscitation. Methods Leukoreduced and nonleukoreduced pRBC units were prepared from human donors and C57/Bl6 mice and stored for up to 42 d and 14 d, respectively. At intervals during storage, MVs were isolated from pRBC units, quantified and characterized based on size, morphology, and levels of proinflammatory cytokines. In additional experiments, mice underwent controlled hemorrhage followed by resuscitation with normal saline (NS) with or without equal numbers of MVs isolated from leukoreduced or nonleukoreduced stored mouse pRBC. Histologic lung sections were evaluated for the presence of tissue edema and inflammatory cells. Results For both human and mouse pRBCs, the number of MVs significantly increased throughout the storage period. There were significantly fewer MVs present in leukoreduced units. The average MV size significantly increased over time and was similar between groups. Levels of interleukin 1α (IL-1α), regulated on activation, normal T cell expressed and secreted (RANTES), and macrophage-derived chemokine (MDC) were lower in MVs from leukoreduced pRBC units as compared with MVs from nonleukoreduced units. Hemorrhaged mice resuscitated with NS with the addition of MV from leukoreduced pRBC demonstrated significantly less pulmonary edema and inflammatory cell recruitment as compared to those resuscitated with NS with the addition of MV from nonleukoreduced pRBC. Conclusions Prestorage leukoreduction of pRBC units reduces the formation and proinflammatory properties of MV, which in turn decreases lung injury secondary to MV from stored pRBC units after hemorrhage and resuscitation.