Objectives: The effect of ionic low osmolar contrast media (ICM) and nonionic iso-osmolar CM (NICM) on acute thrombotic complications of percutaneous coronary intervention (PCI) is subject to controversies possibly related to a potential interaction with anticoagulation regimens. We sought to compare physical and morphological properties of fibrin clots made in the presence of ioxaglate (ICM), iodixanol (NICM) versus control and to evaluate the effect of four anticoagulants used in PCI. Methods and Results: Maximum platelet aggregation (MPA%), maximum elastic modulus (EM, dyne/cm2) fiber density (n/10−5/μm2), and lysis front velocity (nm/sec) of fibrin rich clot (FRC) were measured simultaneously using peripheral blood from 12 patients undergoing elective PCI. We compared the effects of adding iodixanol or ioxaglate or saline (control) to blood with enoxaparin, unfractionated heparin, fondaparinux, and bivalirudin. Iodixanol and ioxaglate led to nonsignificant reduction in MPA compared to control (33.6% ± 16.9%, 28.2% ± 18.9%, and 40.7% ± 13.9%, respectively, P = ns). Fibrin formed with iodixanol was stiffer (42.7 ± 41.9, 18.7 ± 3.7, and 15.9 ± 9 dyne/cm2, P < 0.01) and displayed more fibrin fibers (1089 ± 175, 260 ± 108, and 456 ± 131 n/10−5/μm2, respectively, P < 0.01) than with ioxaglate or control. This resulted in a profound reduction in the lysis front velocity (191 ± 95, 261 ± 112, and 360 ± 153 nm/sec). None of the four anticoagulants displayed any significant interaction on the effect of contrast media. Conclusions: The prothrombogenic effect of iodixanol is related primarily to an increase in fibrin stiffness with subsequent delayed fibrinolysis, something not seen with ioxaglate. Anticoagulation does not appear to have any impact on this fibrin clot abnormalities. © 2011 Wiley-Liss, Inc.