Factor V Leiden with activated protein C resistance is found in up to 5% of the population. It is associated with current adverse pregnancy outcomes. Maternal floor infarction is a lesion in which fibrin is deposited throughout the placenta, leading to necrosis of villi, and (50% of the time) fetal demise. It is also often recurrent. There is no known etiology of maternal floor infarction, nor is there a known treatment. We report a case of a 34-year-old G5, P2 with multiple pregnancy losses, including two fetal deaths. Placental pathology was obtained from one of the losses and was notable for maternal floor infarction. In the index pregnancy, she was evaluated for thrombophilia and found to have a significant protein C resistance of 1.59, consistent with a factor V Leiden. She was treated with low-molecular-weight heparin, enoxaparin, 40 mg twice a day, titrated to achieve an activated factor Xa activity level of 0.2 prior to her next dose. Her pregnancy was unremarkable until 39 weeks, when she developed a decreased amniotic fluid index. A 2995-kg healthy infant was delivered. The placenta showed no evidence of maternal floor infarction. This case demonstrates an association between maternal floor infarction and activated protein C resistance. It is also notable for a successful treatment of recurrent maternal floor infarction with prophylactic heparin. A single case report can only raise a question regarding associations. As we become more familiar with the thrombophilias, we may better understand the association of thrombophilias and placental disease as well as develop successful treatments.