—The effect of plasma lipoprotein fractions (large very-low-density lipoprotein, small very-low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein) on initiation of blood coagulation by supporting factor VII activation or by stimulating monocytes to express tissue factor was investigated in vitro. Endotoxin-free preparations of lipoprotein fractions did not induce functional tissue factor in monocytes, whereas all lipoprotein fractions enhanced tissue factor–independent activation of factor VII by factor Xa and by factors Xa/Va. In contrast, no or only slight enhancement of factor IXa–, factor IXa/VIIIa–, factor XIa–, or thrombin-mediated factor VII activation was observed. The effect of small very-low-density lipoprotein was less than that of large very-low-density lipoprotein, and intermediate-density and low-density lipoproteins caused an even lower but still significant increase of factor Xa– and factor Xa/Va–mediated factor VII activation. When the data were normalized for apolipoprotein B-100 content, differences remained between lipoprotein fractions. In contrast, when phospholipid content was used for normalization, differences between lipoprotein fractions in factor Xa– and factor Xa/Va–mediated factor VII activation disappeared, indicating that phospholipids were involved in factor VII activation. This was supported by enhancement of factor Xa–mediated factor VII activation by synthetic phospholipid vesicles containing negatively charged phospholipids.