Frequency‐Dependent Effects of Verapamil.Introduction:The purpose of this study was to examine the frequency‐dependent effects of verapamil on refractoriness and development of conduction block in the human atrioventricular (AV) node.Methods and Results:To more closely simulate conditions thai would be found when the drug is used clinically, the drug was assessed in the absence of autonomic blockade. Antegrade refractory periods were determined in nine patients before and during the administration of verapamil by constant intravenous infusion. In addition, continuous recordings were made during 30‐second sequences of atrial pacing at a long cycle length alternating with sequences at shorter pacing cycle lengths. Mean verapamil levels were constant throughout the study and averaged 111.6 ± 70.7 ng/mL. In the majority of patients, refractoriness in the atrium prevented determination of the effective refractory period of the AV node in the control state. Therefore, although the effective refractory period of the AV node lengthened with decrease in pacing cycle length in the presence of verapamil, the relative contribution of the change in cycle length itself compared to the effect of verapamil could not be determined. A frequency‐ and time‐dependent change in A‐H interval was found with verapamil during atrial pacing. Kinetic analysis of drug effect on AV nodal function was possible in only three patients; in these three patients the mean time constant for onset of block was 2.9 seconds (range 1.9–4.0 sec). In one patient at a pacing cycle length that did not result in second‐degree AV block, transient periods of alternation between short and long A‐H intervals occurred in the presence of verapamil.Conclusion:Verapamil causes frequency‐dependent block of conduction through the AV node. Since changes in autonomic tone will vary from patient to patient, the actual magnitude of the effects of verapamil will vary as well. This may account for some of the interpatient variability seen with clinical use of this drug, despite comparable blood levels. (J Cardiovasc Electrophysiol, Vol. 3, pp.