The role of innate immunity, e.g., complement activation and cytokine release in the hemodynamic alterations in the course of human septic shock is largely unknown. We prospectively studied 14 consecutive septic shock patients with a pulmonary artery catheter in place. For 3 days after admission, hemodynamic variables and plasma levels of C3a, a product of complement activation, and interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α) were measured 6-hourly. Doses of vasoactive drugs were recorded. Of the 14 patients, 8 died in the ICU. Patients had a hyperdynamic circulation with tachycardia, mild hypotension, increased cardiac index, peripheral vasodilation and myocardial depression. C3a, IL-6 and TNF-α plasma levels were supranormal in 123 of 138 (89%), 132 of 138 (96%) and 83 of 111 (75%) measurements, respectively. Independently of blood culture results, treatment with vasoactive drugs and outcome, mean arterial blood pressure and systemic vascular resistance index were lower when IL-6 levels were higher and left ventricular function was less depressed when C3a levels were higher in the course of septic shock. The TNF-α levels did not invariably relate to peripheral vascular and myocardial function parameters. Our serial observations suggest that, in human septic shock, peripheral vasodilation is most strongly and independently, of all inflammatory factors, associated with IL-6 release, whereas complement activation partly offsets the myocardial depression of the syndrome. Innate immunity factors may thus differ in their contribution to the course of hemodynamic abnormalities of septic shock.