<p>Saliva holds great promise as a background fluid for point-of-care analyte monitoring due to the ease of saliva collection in the field. However, due to the complex composition of human saliva and the associated potential for signal interference, quantification of analytes in minimally processed human saliva can be challenging. Further, analyte concentration in saliva is often at substantially lower levels than in serum. Thus, signal enhancement methods are critical for robust quantification of salivary analytes and specifically in our application of monitoring the anti-seizure drug carbamazepine for guiding therapeutic dosing. In this study, we investigate the use of Nafion™, a perfluorosulfonic acid ion-exchange polymer, as an electrode coating for the electrochemical signal enhancement of carbamazepine in saliva. We show that Nafion™, in combination with the surfactant sodium dodecyl sulfate (SDS), can be critical for carbamazepine detection at the expected therapeutic levels in saliva and we report the optimal mass loading of the polymer on the electrodes. Further, we evaluate multiple methods of SDS and Nafion™ incorporation into our system.</p> Graphical Abstract <p></p>