Human peripheral blood monocytes and mature macrophages were found to produce significant procoagulant activity (PCA), identified as tissue factor, on exposure to a variety of human (K562, HL60, Raji) and murine (TU5, NS-1) transformed cell lines. The monocyte procoagulant response was vigorous, generating PCA to a level nearly comparable to the response to endotoxin, a known stimulant for monocyte PCA. The response was rapid and could be fully elicited, in a dose-dependent fashion, within 4 hr with HL60 and Raji cell lines and within 14 hr with K562, TU5, and NS-1 cells. The monocyte PCA-inducing activity was found to reside in the membrane fraction of transformed cells. Other transformed human (Laz 509, Laz 221, Laz 156, U937, CEM) and murine (L1210, P815, TLX9, WEHI 164) cell lines had little, if any, activity. The induction of monocyte PCA by transformed cells most probably was not due to an allogeneic signal, as 1) the K562 and HL60 cell lines were potent PCA inducers despite the lack of class II histocompatibility antigen expression, whereas Laz 156, which did express HLA antigens, was ineffective; 2) mouse peritoneal macrophages responded with the production of strong PCA to the syngeneic transformed cell lines TU5 and NS-1. The monocyte-macrophage procoagulant response to transformed cell lines appeared to be independent of T lymphocytes. Indeed, monocytes purified on the basis of reactivity with monoclonal antibody Mo2 and sorting or depleted of contaminating T cells by anti-T3 antibody and complement responded similarly to conventional monocyte preparations. The production of tissue factor by monocyte-macrophages in response to exposure to some tumor cells may represent a mechanism whereby blood coagulation is activated in malignancy.