Complete resistance to vitamin K antagonists is a rare but serious condition. It can complicate therapeutic management, especially when direct oral anticoagulants cannot be used. Some single mutations in the VKORC1 gene have been identified in patients partially or completely resistant to vitamin K antagonists. We report the cases of two women in their fifties who presented an unexplained peripheral venous thrombosis. The aetiological assessment did not show any abnormalities. Genetic testing showed that both patients had the VKORC1 5417 GG genotype. The VKORC1 3673 genotype was GG in case 1 and GA in case 2. The two patients showed complete resistance to vitamin K antagonists which required a change in treatment with favourable outcomes. Our goal is to offer optimal care guided by a literature review.