Panic disorder is associated with an elevated risk of cardiovascular disease and sudden death. Individuals with panic disorder have been shown to have reduced variability in heart rate and increased variability in the QT interval on electrocardiogram (ECG), patterns predictive of sudden cardiac death in certain forms of cardiomyopathy. Given that panic disorder patients often hyperventilate during a panic attack, we assessed the effects of voluntary hyperventilation on the ECG utilizing linear analyses of heart rate and QT interval variability. Sixteen symptomatic, medication-free patients underwent hyperventilation challenge. A small subgroup of eight subjects underwent re-challenge after treatment. Pre-treatment, hyperventilation resulted in a decrease in a measure of heart rate variability and an increase in the QT variability index (QTVI; QT variance normalized for mean QT, divided by heart rate variance normalized for mean heart rate). In a remitted state, the QTVI was reduced both during rest and during hyperventilation compared with the respective pre-treatment levels. These findings suggest a possible mechanism explaining increased rates of cardiovascular morbidity and mortality in panic disorder. Moreover, the reduction in QTVI observed post-treatment raises the question of whether treatment might have cardioprotective effects, at least in panic disorder patients who have particular types of co-morbid cardiac disease. Yet these results must be interpreted cautiously; they are preliminary, exploratory and observed in a very small sample without a healthy comparison group.