Epilepsy is one of the most common chronic neurological diseases, and its pharmacological treatment holds great importance for both physicians and national authorities, especially considering the high proportion of drug-resistant patients (about 30%). Lacosamide (LCM) is an effective and well-tolerated new-generation antiepileptic drug (AED), currently licensed as add-on therapy for partial-onset seizures. However, LCM mechanism of action is still a matter of debate, although its effect on the voltage sensitive sodium channels is by far the most recognized. This study aimed to retrospectively analyze a cohort of 157 drug-resistant patients treated with LCM to describe the most common and effective therapeutic combinations and to investigate if the LCM can affect also GABAA-mediated neurotransmission as previously shown for levetiracetam (LEV). In our cohort, LEV resulted the compound most frequently associated with LCM in the responder subgroup. We therefore translated this clinical observation into the laboratory bench by taking advantage of the technique of "membrane micro-transplantation" in Xenopus oocytes and electrophysiological approaches to study human GABAA-evoked currents. In cortical brain tissues from refractory epileptic patients, we found that LCM reduces the use-dependent GABA impairment (i.e., "rundown") that it is considered one of the specific hallmarks of drug-resistant epilepsies. Notably, in line with our clinical observations, we found that the co-treatment with subthreshold concentrations of LCM and LEV, which had no effect on GABAA currents on their own, reduced GABA impairment in drug-resistant epileptic patients, and this effect was blocked by PKC inhibitors. Our findings demonstrate, for the first time, that LCM targets GABAA receptors and that it can act synergistically with LEV, improving the GABAergic function. This novel mechanism might contribute to explain the clinical efficacy of LCM-LEV combination in several refractory epileptic patients.