OBJECTIVE Contrast agents have been reported to influence the blood clotting system to an extent depending mainly on whether the compounds are ionic or nonionic. The objective of the current series of studies was to determine interspecies differences; the effect of variable incubation times; and the effect on thromboplastin times (TPT) of adding heparin to a number of x-ray and magnetic resonance imaging (MRI) contrast agents. In addition, the stability of clots formed in the presence of iopromide was studied. In a final experiment, the effect of the contrast agents on the bleeding time was studied in rats. METHODS Nine x-ray and three MRI contrast agents were used in the study. Thromboplastin times was determined in platelet-poor plasma of humans, rats, rabbits, or dogs using calcium (Ca) thromboplastin from human placenta or rabbit brain and lung tissue and incubation times as long as 4 hours. Bleeding times were determined in rats 5 minutes, 4 hours, 24 hours, and 48 hours after intravenous injection of the contrast agents by making a small incision into the tail of the animal, immersing the tail in saline, and measuring the time period during which small blood streaks were visible. RESULTS Nonionic contrast agents (x-ray and MRI) increased the TPT by a factor of 1.5 to 2, whereas ionic compounds prolonged TPT by a factor of > 3. Thromboplastin times increased in the order of dog < rabbit < rat < human 2- to 4-fold. However, the ranking of different contrast agents remained unchanged. Prolongation of bleeding time lasted as long as 24 hours for some contrast agents. Clots formed in the presence of iopromide were unstable and did not absorb the contrast agent. CONCLUSIONS The animal models used in the current series of studies seem to be valid for predicting the effect of contrast agents on the blood clotting system in humans.