To test the possibility that different doses of heparin or other sulfated polysaccharides are required to inhibit thrombosis initiated by different stimuli, we compared the effects of heparin (HEP), pentosan polysulfate (SP54) and dermatan sulfate (DS) on the inhibition of thrombus formation induced by either I) tissue thromboplastin; II) thrombin; or III) factor Xa. Inhibition of thrombus formation induced by the stimuli was measured in a rabbit jugular vein hypercoagulation/stasis model. First, we determined the minimum dose of each sulfated polysaccharide which inhibited tissue thromboplastin-induced thrombus formation by ∼75%, and then compared the relative effectiveness of this dose to prevent thrombus formation initiated with the other two stimuli. HEP and SP54 were less effective when thrombin was the thrombogenic stimulus, while DS was more effective. HEP was the most effective agent when factor Xa was the stimulus. We conclude that the antithrombotic effectiveness of a given dose of a sulfated polysaccharide may vary depending on the stimulus which initiates thrombus formation.