Seizures may prompt autonomically mediated changes in heart period. Heart period variability (HPV) is a sensitive tool for quantification of autonomic control over the cardiac cycle. We used analysis of HPV to evaluate changes in the time and frequency domain autonomic regulation of heart period during seizure activity in 44 seizures from 12 patients with epilepsy: 16 % of seizures were associated with changes in heart rate and variability preceding behavioral and surface electroencephalographic (EEG) onset. Patients with consecutive partial seizures had variable HPV changes. Seizures of left-sided EEG onset were associated with no change or a decrease in the power of the 0.2- to 0.4-Hz band, whereas seizures of right-sided EEG onset were associated with no change or a decrease in the power of the 0.04- to 0.12-Hz band. We believe that time- and frequency-domain analysis of HPV may provide valuable information about the temporal and spatial onset of seizure activity. Additional study using invasive EEG recordings will be needed to evaluate the reliability of HPV to lateralize or localize seizure foci.