The mechanism of isolated thrombocytopenia in septicemia is unknown, but compensated disseminated intravascular coagulation (DIC) has been suggested as a possible cause. To investigate this possibility, platelet counts and sensitive assays for in vivo thrombin and plasmin generation, including fibrinogen gel chromatography and fibrinopeptide A (FPA) assays, were obtained on 31 septicemic patients. Fifteen of 17 patients with gram-negative septicemia and 8 of 14 patients with gram- positive septicemia had thrombocytopenia. Platelet survival studied demonstrated a decreased platelet survival. In 11 of 12 patients with severe thrombocytopenia (platelet count less than 50,000mul), there was laboratory evidence of intravascular coagulation. In contrast, there was little evidence of intravascular coagulation in 8 of 11 patients with moderate thrombocytopenia (platelet counts 50,000 to less than 150,000/mul) or in 7 of 8 patients with normal platelet counts. This report indicates that while DIC accompanies thrombocytopenia in many patients with severe thrombocytopenia, there is frequently little evidence for intravascular coagulation in patients with moderate thrombocytopenia. It is apparent that factors other than intravascular thrombin must play a role in producing the thrombocytopenia of septicemia.