ABSTRACT The tissue factor (TF) pathway is the primary mechanism for initiation of blood coagulation. Circulating blood contains TF which originates mainly from monocytes and is thrombogenic. The presence of somatostatin (SMS) receptors on monocytes suggests the possibility that SMS may regulate TF synthesis and/or release. Circulating TF procoagulant activity (TF-PCA), factor VIIa activity (FVIIa) (clotting assays), TF antigen (TF-Ag, ELISA), prothrombin fragment 1.2, thrombin-antithrombin complexes (ELISAs), CD40 ligand expression on platelets and monocyte-platelet aggregates (flow cytometry) were determined in blood from normal volunteers undergoing 24 h of basal glucose/basal insulin (BG/BI) clamps and high glucose/high insulin (HG/HI) clamps with and without SMS. Infusions of SMS under basal conditions (BG/BI) raised TF-PCA 1.8-fold (p < 0.03) TF-Ag 2.3-fold (p < 0.001), TF expression on monocytes by 36% (p < 0.001) and decreased plasma levels of FVIIa by 30% (p < 0.001). Infusion of SMS reduced the 8.6-fold HG/HI induced increase in TF-Ag by 26% and the 8.6-fold increase in TF-PCA by 100%. SMS also prevented the 60% increase in TF expression on monocytes, the 2.2-fold increase in F1.2, the 40% increase in CD40L expression on platelets and the 17% increase in monocyte-platelet aggregates seen during HG/HI. We conclude that SMS completely prevented HG/HI induced TF activation in normal volunteers and may be of use to reduce the procoagulant state and acute vascular events in hyperinsulinemic insulin resistant patients with type 2 diabetes.