The presence of neutrophils within the graft has been widely emphasized as a characteristic feature of hyperacute rejection, and analogies have been drawn to the Arthus reaction, in which neutrophils are essential mediators of tissue damage. To evaluate the role of neutrophils as mediators of graft destruction in hyperacute rejection, we studied a series of 16 heterotopic ACT strain rat cardiac allografts in skin-presenitized Lewis strain recipients, all of which recieved prior treatment with cyclophosphamide and methotrexate or heterologous rabbit antirat polymorphonuclear globulin. Fourteen recipients showed significant depression in levels of circulating neutrophils prior to transplant, and neutrophils were not detected in 13 allogrates at the time of functional rejection. There was no abrogation of hyperacute rejection in this series and the characteristic pattern of vacular and myocardial damage was not altered by the absence of neutrophils from the graft. Although the possibility that neutrophil-derived agents may contribute to late graft destruction cannot be excluded, this study has shown that neutrophils are neither essential nor specific participants in hyperacute allograft rejection in this model.