We examined the effect of the lipoproteins on the activation of human factor X in an in vitro system containing purified human factor VII, low levels of tissue factor and calcium ions. In the absence of the lipoproteins the maximum activation was achieved within 10 min of the start of incubation; after this period the formation of factor Xa ceases. When very low-density lipoproteins, low-density lipoproteins or high-density lipoproteins were present at normal or subnormal plasma concentrations, the factor Xa generated was almost doubled after 10 min. This increase could be abolished by treating each lipoprotein subfraction with the phospholipase A2; hence, the treated lipoproteins lowered the factor Xa activity. We conclude that the phospholipids favor factor Xa formation and protect the tissue factor/factor VIIa/factor Xa complex from a potent inhibitor contained in the lipoprotein subfractions.