Thromboembolic events remain a significant issue in mechanical circulatory support. The aim of this study was to evaluate the potential benefit of surface modification in total artificial hearts (TAHs) using polymeric phospholipids (biomembrane mimicry). For this purpose, pneumatic TAHs (vacuum formed pellethane housing, hard double flap hinged inflow valves, soft trileaflet polyurethane outflow valves) had their blood-exposed surfaces either modified with polymeric phospholipids or unmodified before evaluation in bovine experiments. Orthotopic implantation of the TAHs was performed with cardiopulmonary bypass (CPB) using tip-to-tip heparin surface coated perfusion equipment and very low systemic heparinization (50 IU/kg bodyweight). After weaning from CPB and stabilizing hemodynamics, circulating heparin was neutralized with protamine (1:1). All animals were totally supported for 24 hours before elective sacrifice. No heparin was added at any time during support. Mean activated coagulation time (ACT) was 167 ± 24 s at baseline before heparinization for CPB, 330 ± 45 s at the end of CPB, 181 ± 25 s after 1 hour of support, 180 ± 31 s after 6 hours, and 185 ± 28 s after 18 hours. After explanation, the TAHs perfused without anticoagulation were carefully analyzed. Atrial cuff coverage with red clot was 30 ± 21% for artificial surfaces modified by biomembrane mimicry versus 100 ± 0% for standard control surfaces (p < 0.01). The number of macroscopic deposits found on the inflow valves was 1.33 ± 0.47 for surfaces modified by biomembrane mimicry versus 3.83 ± 1.86 for standard control surfaces (p < 0.05). Likewise, on the outflow valves the number of macroscopic deposits was 0.00 ± 0.00 for surfaces modified by biomembrane mimicry versus 1.00 ± 0.81 for standard control surfaces (p < 0.05). We conclude that presence and distribution of red clots and other macroscopic deposits are significantly different for artificial surfaces with biomembrane mimicry versus standard control surfaces. Application of the biomembrane mimicry concept has the potential to provide improved TAHs. ASAIO Journal 1999; 45:211–214.