A series of poly(alpha-amino acid)s with controlled chemical variations were investigated in order to assess the effect of different chemical moieties upon arterial thrombosis. The gross implant surface properties ranged from hydrophobic to hydrophilic ionic and nonionic. The materials were tested by implantation within canine femoral and carotid arteries. Results were compared with the response to the polyurethane Biomer. The changes in implant surface chemistry elicited a range of response that varied from intense thrombosis and rapid vessel occlusion to minimal thrombosis and endothelialization. The results showed that no simple relationship exists between a gross surface property, such as hydrophobicity, and the degree of thrombosis resistance. Some hydrophobic and hydrophilic materials were found to have good thrombosis resistance, while others were found to have poor thrombosis resistance. Leukocytes were shown to play an important role in both initial thrombosis and endothelialization. The major difference between materials that progressed to rapid vessel occlusion and materials that remained patent was the degree of direct leukocyte adherence and spreading on the implant surface prior to extensive platelet aggregation (less than 30 min). It was consistent for both hydrophobic and hydrophilic materials that the lack of direct leukocyte adherence to the implant surface was associated with intense thrombosis and rapid vessel occlusion. Conversely, the presence of numerous leukocytes directly adherent to either hydrophobic or hydrophilic surfaces appeared to have a moderating effect upon thrombosis and vessels with these implants remained patent. In instances when thrombosis was nonocclusive, the surfaces of the thrombi became endothelialized, primarily through the transformation of mononuclear leukocytes into endothelial cells. This article includes a hypothetical model representing the sequence of events and alternative pathways occurring at the blood-material interface, with special attention given to the involvement of leukocytes in arterial thrombosis.