Hypofibrinogenemia reduces experimental venous thrombosis, but the impact on arterial thrombosis remains unknown. In a cohort of patients with congenital fibrinogen disorders, 19/264 (~7%) patients developed arterial thrombosis, including 4/41 (~10%) patients with hypofibrinogenemia. However, 0/8 patients with fibrinogen aC-region truncation mutations reported arterial thrombosis over 286 patient-years. To analyze the impact of hypofibrinogenemia and the fibrinogen aC-region on arterial thrombosis, two mouse models were employed: 1) wildtype mice treated with lipid nanoparticles encapsulating siRNA against fibrinogen (siFga) and 2) Fga270/270 hypofibrinogenemic mice expressing fibrinogen with a truncated aC-region. While siFga-treated hypofibrinogenemic mice developed occlusive carotid artery thrombi similarly to controls, Fga270/270 mice displayed suppressed carotid thrombosis following FeCl3 challenge, indicating loss of the aC-region but not hypofibrinogenemia alone reduces arterial thrombosis. To determine if protection from arterial thrombosis in Fga270/270 mice was linked to loss of aC-region-platelet glycoprotein VI receptor (GPVI) interaction, platelet GPVI was depleted by JAQ1 antibody administration. JAQ1-treated wildtype mice were protected from arterial thrombosis following 5% FeCl3 but not 10% FeCl3 challenge. Interestingly, JAQ administration suppressed arterial thrombosis in siFga-treated mice but did not enhance protection in Fga270/270 mice following 10% FeCl3 challenge. Our studies suggest the fibrinogen aC-region promotes arterial thrombosis in hypofibrinogenemic conditions.