BACKGROUND The incidence of sudden cardiac death is highest in the morning hours. Although a circadian variation in myocardial ischemia may be responsible in part for this observation, other factors also may be contributory. It is not known whether a circadian variation in ventricular refractoriness exists that may be related to the increased morning incidence of sudden cardiac death. RESULTS Nine subjects with primary conduction system disease, no evidence of structural heart disease, and permanent pacemakers were studied. Autonomic nervous system function as assessed by tilt table and baroreflex sensitivity testing was normal in all subjects. Using noninvasive programmed stimulation, ventricular effective refractory periods were measured hourly for 24 hours. Potassium, epinephrine, and norepinephrine levels also were measured hourly. In a subset of five subjects, ventricular refractory periods were again measured hourly over 24 hours during beta-blockade. A significant circadian variation in ventricular refractoriness was noted, with a mean difference between the shortest and longest refractory periods in individual subjects of 23 ms and 21 ms at drive cycle lengths of 600 ms and 400 ms, respectively. In eight subjects, the shortest refractory periods observed over 24 hours occurred within 2 hours of waking (random probability < 10(-8)). Adjustment of refractory period data according to the hour of waking resulted in a better correlation between ventricular refractory periods and time. Although a significant circadian variation was observed in potassium and catecholamine levels, neither was an independent predictor of refractory periods after adjustment for the hour of waking. The adjusted time of day was the only significant (P < .0001) independent predictor of refractory periods. beta-Blockade abolished the circadian variation in ventricular refractory periods. CONCLUSIONS A significant circadian variation in ventricular refractory periods exists. Maximal shortening between hourly refractory periods as well as the shortest refractory periods occur in the early morning hours when the incidence of sudden cardiac death is greatest. Fluctuations in beta-adrenergic tone appear to be largely responsible for this phenomenon.