Background <p>Previous studies on cenobamate (CNB) have generally reported neutral to positive effects on objective cognitive performance in patients with epilepsy, but are limited to dosages up to 250 mg/day. However, a case report (Witt et al. in Neurocase 30:91–96, 2024) noted severe memory deterioration at 400 mg/day.</p> Objective <p>The purpose of this study was to examine dose-dependent effects of CNB on cognition.</p> Methods <p>In this retrospective longitudinal real-world study, executive functions and episodic memory were assessed in adult patients with pharmacoresistant epilepsy during CNB therapy and compared with baseline. Subgroups were stratified by daily CNB doses of ≥ 300 mg versus &lt; 300 mg. Executive functions were assessed using the EpiTrack^®, verbal memory via the VLMT or an abbreviated version, and figural memory with the DCS-R.</p> Results <p>The study included 84 patients, 24 (28.6%) of them with a CNB dose of ≥ 300 mg. With a mean CNB dose of&#xa0;200.6 ± 114.3 mg (range 12.5–400.0 mg), seizure freedom was achieved in 11.9% with no significant difference between the lower and the higher dose group. Repeated measures analysis of covariance (ANCOVA) revealed a significant decline in executive functions at ≥ 300 mg (<i>n</i> = 84; <i>F</i> = 6.35, <i>p</i> = 0.014) compared to baseline. Changes were correlated with CNB dose (<i>r</i> = −&#xa0;0.31, <i>p</i> = 0.004). Individual level analyses indicated that 50.0% of patients on higher versus 16.7% on lower CNB doses deteriorated according to reliable change indices (RCI). In a subgroup undergoing extensive memory testing, verbal retention showed a significant negative, dose-independent effect at the group level (<i>n</i> = 22; <i>F</i> = 7.95, <i>p</i> = 0.011), with intraindividual declines in 28.6% (≥ 300 mg) versus 13.3% (&lt; 300 mg). Other memory parameters were unaffected.</p> Conclusions <p>The results of this real-world study investigating objective cognitive performance under CNB suggest possible, partially dose-dependent negative effects of CNB on cognition. Daily CNB doses of ≥ 300 mg were associated with a significant decline in executive functions. Furthermore, a dose-independent negative effect on verbal retention was observed in a subgroup of patients undergoing extensive memory assessment. Given the limitations of retrospective audits, our findings prompt further, larger scope studies to confirm the results. However, a careful balance between seizure control at the lowest CNB dose possible and potential cognitive side effects appears advisable, which requires the implementation of cognitive monitoring in standard care where possible.</p>