—Recent studies have shown that antiphospholipid (aPL) enhances expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin on endothelial cells (ECs) and that these effects are correlated with increased adhesion of leukocytes to endothelium in cremaster muscle in vivo and with thrombosis in a mouse model. Activation of ECs by aPL may create a hypercoagulable state that precedes and contributes to thrombosis in patients with aPL syndrome (APS). This study proposed to examine whether this in vivo activation of ECs and enhanced thrombosis by aPL are mediated by ICAM-1, P-selectin, or VCAM-1. The dynamics of thrombus formation and the number of adhering leukocytes were studied in ICAM-1–deficient (ICAM-1^−/−) mice or ICAM-1–/P-selectin–deficient (ICAM-1^−/−/P-selectin^−/−) mice treated with affinity-purified aPL antibodies (ap IgG-APS) or with control IgG and compared with wild-type mice treated in a similar fashion. In another set of experiments, the adhesion of leukocytes to cremaster muscle and the dynamics of thrombus formation were studied in CD1 mice treated with aPL or control IgG before and 30 minutes after intravenous infusion with 100 μg monoclonal antibody anti–VCAM-1. The results indicate that the enhanced adhesion of leukocytes to endothelium in wild-type mice was significantly reduced in ICAM-1^−/− and completely abrogated in ICAM-1^−/−/P-selectin^−/− mice treated with ap IgG-APS compared with wild-type mice treated with ap IgG-APS (6.9±2.3, 0.4±0.4 versus 35±12, respectively). More importantly, this correlated with a significant reduction in thrombus size compared with wild-type mice treated with ap IgG-APS (895±259 μm², 859±243 μm² versus 3816±672 μm², respectively). Infusion of the mice with anti–VCAM-1 antibodies significantly reversed the enhanced adhesion of leukocytes (14.9±3 to 11.3±2.1) and thrombus size 3830±1008 μm² versus 876±548 μm²) in mice treated with ap IgG-APS. The data indicate that ICAM-1, P-selectin, and VCAM-1 expression are important in thrombotic complications by aPL antibodies and may provide novel targets for therapy in patients with APS.