| Summary: | <b>Background:</b> Cenobamate is a novel antiseizure medication with potential interactions involving cytochrome P450 enzymes, including CYP2C19. Genetic variability in CYP2C19 may influence drug metabolism and tolerability, although its clinical relevance in cenobamate-treated patients remains unclear. <b>Methods:</b> We conducted a single-center retrospective study including 48 adults with drug-resistant epilepsy treated with cenobamate. Patients were stratified by concomitant use of CYP2C19-substrate ASMs (patients with CYP2C19 substrates vs. patients without CYP2C19 substrates). CYP2C19 genotype was classified into metabolizer phenotypes. Adverse events (AEs) were categorized as potentially CYP-mediated or likely unrelated to CYP-mediated pharmacokinetic mechanisms based on clinical assessment, temporal association, and known pharmacological interaction profiles. Associations were explored using descriptive statistics and regression models. <b>Results:</b> Overall, 58.3% of patients received CYP2C19-substrate ASMs. AEs were more frequent among patients with CYP2C19 substrates (71.4% vs. 20.0%; <i>p</i> = 0.001), with potentially CYP-mediated AEs observed only in this group (32.1% vs. 0%; <i>p</i> < 0.001). Intermediate metabolizers showed a higher proportion of potentially CYP-mediated AEs (87.5%; <i>p</i> < 0.001). This pattern was not observed in patients without CYP2C19 substrates. Regression analyses suggested increased risk in intermediate metabolizers, although estimates were imprecise and should be considered exploratory. <b>Conclusions:</b> An exploratory association between CYP2C19 variability and AE occurrence was observed in patients treated with cenobamate combined mainly with clobazam and other CYP2C19-substrate ASMs. Intermediate metabolizers may represent a higher-risk subgroup, but these preliminary findings require prospective confirmation with pharmacokinetic monitoring.
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