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<b>Background</b>: To assess associations between possible dysfunction of autonomic cardiovascular modulation and hemispheric localization, seizure frequency, disease duration, and antiseizure medication (ASM) in temporal lobe epilepsy (TLE). <b>Methods</b>: In this prospective observational study, cardiovascular autonomic modulation was monitored in 31 patients with TLE (12 patients with right TLE, 19 patients with left TLE). From 5 min time series of R-R intervals (RRI) and blood pressure (BP) recordings, we calculated autonomic parameters of sympathetic, parasympathetic, and total autonomic cardiovascular modulation. Data were compared to those of 30 healthy volunteers. Subgroup analyses were performed according to (1) disease localization (right vs. left hemispheric TLE), (2) seizure frequency (< vs. >1/month) and disease duration (< vs. >10 years), (3) number of ASMs, and (4) participants' age (< vs. >30 years). <b>Results</b>: Between right TLE patients, left TLE patients, and controls, there were no significant differences in the assessed bio-signals. Parameters of sympathetic and total autonomic modulation were slightly lower in right TLE patients than in controls. Additionally, reduced vagal modulation was observed in right TLE patients taking three ASMs or not taking any ASMs at all (applicable to one patient) compared to healthy controls. In general, TLE patients with <1 seizure/month showed lower parameters of sympathetic modulation than healthy controls, with differences reaching statistical significance in left TLE patients. In contrast, parameters reflecting vagal tone showed insignificantly, yet consistently, lower values in left TLE patients with increasing seizure frequency. Alterations in autonomic cardiovascular modulation observed across age-matched subgroups were comparable. <b>Conclusions</b>: A trend towards lower values of sympathetic modulation in patients with right TLE supports previous findings suggesting right hemispheric mediation of sympathetic regulation. A decrease in parasympathetic modulation with increasing seizure frequency underscores the importance of sufficient seizure control in order to prevent autonomic complications. In contrast, the absence of significant associations between disease duration and autonomic alterations suggests that epilepsy exerts an early and clinically relevant effect on the autonomic nervous system. Due to comparable alterations in autonomic modulation in a patient without antiseizure medication and in patients undergoing polytherapy, ASM side effects may not account solely for the observed autonomic dysregulation of our TLE patients.