Acetaminophen has been one of the most serious electrochemical interferences to oxidase-based amperometric biosensors that measure H2O2. A study was carried out to investigate various polymer materials for their selectivity as the sensor inner membrane. A composite membrane of cellulose acetate and Nafion was found to eliminate acetaminophen and other electrochemical interferences effectively while at the same time maintaining reasonable diffusivity for hydrogen peroxide. The excellent in vivo performance of the sensor was attributed not only to significantly reduced steady-state sensitivity to acetaminophen but also to very slow acetaminophen response. These features, combined with rapid acetaminophen clearance pharmacokinetics, led to the decreased response as demonstrated in the rat.