Various radiographic contrast agents have anticoagulant or prothrombotic properties. Ionic agents are reported to have greater antithrombotic potential while nonionic agents are considered more thrombogenic. Some agents alter fibrin structure and bind to platelets in purified systems. This study compared the effects of iohexol, a nonionic agent, and iothalamate, an ionic agent, on fibrin assembly, clot structure, platelet function and clot dissolution in plasma. Plasma gels containing increasing concentrations of iothalamate were composed of thinner fibers with decreased fiber mass/ length ratios (μ) and reduced gel turbidity. Such clots were more rigid and more resistant to fibrinolysis induced by tissue plasminogen activator (tPA). Gel elastic modula increased from 10,000 to 27,000 dyn/cm² as iothalamate concentration increased from 0 to 20 mM. 50% lysis time increased from 800 to 1,250 s with the addition of 10 mM iothalamate. At 20 mM, iothalamate had no effect on ADP-induced platelet aggregation but prolonged the lag phase seen with collagen-induced aggregation. Platelet force development increased from 15,300 to 20,400 dyn with 20 m_M iothalamate. The effects of iohexol were similar. Gel optical density dropped from 0.50 to 0.32, μ fell from 3.3 to 2.2 × 10¹³ D/cm, and elastic modulus rose from 11,000 to 24,000 dyn/cm² as iohexol concentration was increased from 0 to 20 mM. Clots formed in the presence of 60 mM iohexol and tPA did not dissolve in 72 h while control clot 50% lysis time was 450 s. At concentrations ≥ 40 mM, iohexol completely blocked collagen-induced platelet aggregation. Platelet force development increased from 7,660 to 19,600 with 40 mM iohexol. Contrast media possess profound fibrin-altering activities in plasma. Fibrin formed in the presence of some agents may be significantly more resistant to fibrinolysis.