The degree of cell and organ damage in clinical and histologic studies of patients dying oL Lassa fever has been insufficient to explain thc catastrophic shock characteristic of the fatal illness. To explore this issue further, we conducted a study on the evolution of shock in three Lassa virus-infected rhesus monkeys. By the sixth day after infection a marked progressive reduction of in vitro platelet aggregation occurred despite normal numbers of circulating platelets and a normal platelet survival time and was accompanied by loss of prostacyclin production by postmortem endothelium. Both of these functlons rccovered rapidly in a surviving animal. There was no evidencc of disseminated intravascular coagulation, nor were clotting factors significantly abnormal. We observed association of viral antigen with neutrophils and progressive neutrophilia. Viremia was not reduced by a brisk antibody response in our animals, and there was a general depresslon of response to milogens in mixed lymphocyte stimulation assays. Our findings suggest that shock in Lassa fever is due to biochemical dysfunctions of platelets and endothelial cells and results from loss of intravascular plasma volume, effusions, and hemorrhage.