Lipoxin A₄ (LXA₄) and aspirin‐triggered 15‐epi‐LXA₄ are potent endogenous lipid mediators thought to define the inflammatory set‐point. We used single prophylactic administrations of a synthetic aspirin‐triggered lipoxin A₄ signal mimetic, ATLa, to probe dynamics of early host‐donor interactions in a mouse model for the inflammation‐associated multifactorial disease of allogeneic bone marrow transplant (BMT) ‐induced graft‐vs.‐host disease (GvHD). We first demonstrated that both host and donor are responsive to the ATLa signals. The simple and restricted regimen of a single prophylactic administration of ATLa [100 ng/mL to donor cells or 1 µg(∼50 µg/kg) i.v. to host] was sufficient to delay death. Clinical indicators of weight, skin lesions, diarrhea and eye inflammation were monitored. Histological analyses on day 45 post‐BMT showed that the degree of cellular trafficking, particularly neutrophil infiltrate, and protection of end‐organ target pathology are different, depending on whether the host or donor was treated with ATLa. Taken together, these results chart some ATLa protective effects on GvHD cellular dynamics over time and identify a previously unrecognized effect of host neutrophils in the early phase post‐BMT as important determinants in the dynamics of GvHD onset and progression.—DevchandP. R., SchmidtB. A., PrimoV. C., ZhangQ.‐Y., ArnaoutM. A., SerhanC. N., NikolicB. A synthetic eicosanoid LX‐mimetic unravels host‐donor interactions in allogeneic BMT‐induced GvHD to reveal an early protective role for host neutrophils. FASEB J. 19, 203–210 (2005)