To analyze unique molecular differences between normal and neoplastic cells, we have examined host responses to tumor cells. The present study provides the first evidence for an innate rapid recognitive response of the lymphoid system to some syngeneic tumors. The lymphoid procoagulant (PCA) response, a T cell-instructed monocyte response that activates proteases of the coagulation cascade culminating in thrombin formation, is considered a component of classic delayed-type hypersensitivity responses. We have demonstrated that three syngeneic rat mammary carcinomas elicit this cellular response in vitro in lymphoid cells of the unimmunized rat. The response was rapid, reaching maximum within 6 hr. Analysis was compounded by the constitutive PCA activity of some tumors; however, the PCA product produced in the response to tumor challenge in vitro was newly biosynthesized and was of lymphoid cell origin, differing from the PCA of tumor cells. The lymphoid PCA response was prothrombinase-like and did not require vitamin K for biosynthesis, nor were other gamma-carboxylation-dependent extrinsic pathway proteases other than prothrombin required for thrombin generation. Both in vivo and in vitro derived mammary carcinoma cells elicited the response, whereas a fibrosarcoma and nontransformed syngeneic cells did not. Tumor shed substances, which were devoid of PCA and sedimentable only in part at 100,000 X G, induced this cellular response. The same stimuli shed from tumor cells did not directly elicit a PCA response from elicited peritoneal macrophages; however, in the presence of T lymphocytes a PCA response of these macrophages was produced. This study provides novel information to indicate that a T-enriched lymphocyte-dependent monocyte-macrophage response to some tumors, before effective in vivo immunization, may participate in initial local protease generation and fibrin deposition, both thought to play a significant role in the local pathobiology of tumors.