To our knowledge, the effect of plasmapheresis on the anti-factor Xa activity of enoxaparin has never been reported. We describe a 13-year-old, obese (92-kg) girl who was treated with enoxaparin for a pulmonary embolism while receiving plasmapheresis for suspected autoimmune encephalitis and who experienced clinically significant reductions in anti-factor Xa activity after plasmapheresis. She received five courses of plasmapheresis, with the final two administered during treatment with enoxaparin. Her anti-factor Xa concentrations were highly variable, and we hypothesized that plasmapheresis was affecting these levels. To test this hypothesis, anti-factor Xa concentrations were measured before and immediately after the patient's last plasmapheresis treatment, and then again 2 days after plasmapheresis. The rate of anti-factor Xa activity decline was 0.28 IU/mL/hour with plasmapheresis and only 0.088 IU/mL/hour on the day without plasmapheresis, representing a greater than 3-fold difference. The changes in anti-factor Xa activity due to plasmapheresis altered the final enoxaparin dosage required to remain in the therapeutic range of 0.5-1 IU/mL (0.98 mg/kg/dose while receiving plasmapheresis vs 0.69 mg/kg/dose without plasmapheresis). Our patient's data suggest that plasmapheresis can significantly alter enoxaparin's anticoagulant effect as measured by anti-factor Xa concentrations, which could cause a decreased anticoagulant effect during plasmapheresis and an increased risk of bleeding on plasmapheresis discontinuation. If concurrent enoxaparin-based anticoagulation and plasmapheresis are necessary, close monitoring of anti-factor Xa levels is advisable. Dose escalations and reductions of enoxaparin may be necessary when initiating and discontinuing plasmapheresis, respectively.