The purpose of this study was to evaluate the angiographic and histopathologic changes in the superficial femoral artery (SFA) in heparinized sheep shortly after catheterization with an 8-Fr sheath and manual compression hemostasis either with standard manual compression (SMC) or with the use of a procoagulant chitosan-based HemCon Bandage. The evaluation was done in 38 SFAs of 19 heparinized (100 mg/kg) sheep. After a 5-min catheterization with an 8-Fr sheath, a 5-min compression was applied. Follow-up angiograms to evaluate hemostasis were done immediately after release of compression and then at 2.5-min intervals until no extravasation was present. Compression was reapplied between angiograms. Final angiograms were performed approximately 30 min after hemostasis and after 3 min of passive flexion and extension of sheep hind limbs. Sheep were then euthanized and SFA specimens with surrounding tissues excised for histopathologic evaluation. Both types of compression caused similar changes in the catheterized SFAs. Follow-up angiograms showed mild arterial narrowing in 14 SFAs and intraluminal clots in 9 SFAs. Histology revealed periarterial hematoma in all 38 specimens. Intraluminal thrombi consisting predominantly of platelets and fibrin were present in 32 SFAs. Their size varied from superficial elevations (8 arteries) to medium-sized, 1- to 2-mm, polypoid protrusions (15 arteries) to large polypoid clots, 3-4 mm long (9 arteries). In six SFAs, the arterial access sites were not included in the obtained specimens. In conclusion, hemostasis with manual compression is achieved in the acute phase by formation of a predominantly platelet-fibrin thrombus occluding the arterial wall access site and often extending significantly into the arterial lumen. The healing process of arterial access sites should be explored several days after catheterization.