Minipigs are frequently used in (neuro-)interventional research. Longitudinal experiments may require repeated vessel access via the femoral artery. Anticoagulation and incompliance of the animals necessitates the use of a vascular closure device (VCD). The effects of the Angio-Seal VCD in minipigs were longitudinally assessed. Minipig (42±8.4 kg body weight) femoral arteries were sealed using the 8F (n = 6) or 6F (n = 7) Angio-Seal VCD. The pre-interventional femoral artery diameter was 5.1±0.4 mm (4.3-5.8 mm). Sealed puncture sites were analysed angiographically as well as by computed tomography angiography (CTA) for a mean period of 14.1±8.0 weeks (1-22 weeks). All animals were constantly treated with acetylsalicylic acid (ASS) (450 mg/d (n = 7) or 100 mg/d (n = 1)) and clopidogrel (75 mg/d (n = 8)). Non-instrumented (n = 2) and arteries sealed using the VCD (n = 2) were examined histologically. No postoperative hemorrhagic complications were observed. Three arteries were occluded after VCD placement (1 animal diagnosed after 4 weeks (8F), 2 animals after 1 week (6F)) and remained so until the end of the experiments after 22, 12 and 4 weeks, respectively. In one artery a 50% stenosis 8 weeks after application of a 6F Angio-Seal was detected. In 69.2% (n = 9) the VCD was applied without complications. Histopathological analysis of the sealed arterial segments showed subtotal obliteration of the vessel lumen, formation of collagenous tissue and partial damage of the internal elastic lamina. The Angio-Seal VCD prevents relevant hemorrhagic complications in minipigs treated with dual platelet inhibition, but is associated with increased vessel occlusion rates.