An injection of TNF in mice induced profound thrombocytopenia, due to an increase of platelet consumption, that was evident after 1 h and lasted for 3 days. This process was evident in mice that were genetically deficient in TNFR2 (p75) but not in mice lacking TNFR1 (p55), indicating that the process is mediated by TNFR1-bearing cells. To explore the site of action of TNF, labeled platelets from TNFR1 -/- or +/+ donors were transferred to TNFR1 -/- or +/+ recipients. TNF induced the consumption of platelets from TNFR1 -/- donors when injected into +/+ recipients, while platelets from +/+ donors were not consumed when present in TNFR1 -/- recipients; this finding indicates that TNF acts on the TNFR1 of host cells but does not act on platelets. The expression of TNFRs is consistent with this interpretation, since TNFRs were not detected on platelets by flow cytometry. In megakaryocytes, the expression of TNFR1 was detected by immunohistochemistry. These results indicate that TNF induces platelet consumption by acting not on platelets directly but on the TNFR1 of other cells, presumably increasing the release of factors with agonist activity for platelets.