The electrophysiology of antidromic reentry, a less common phenomenon than orthodromic reentry, remains a poorly understood aspect of the Wolff-Parkinson-White (WPW) syndrome. We used a pacing model of ventricular preexcitation in patients without WPW, so that electrophysiological events in the normal pathway during atrial extrastimulation (A1-A2 technique) could be precisely delineated without the obscuring effect of an actual accessory pathway. Ventricular preexcitation was simulated by an A1-V1 sequential basic drive with A2-V2 extrastimulation at progressively shorter A1-A2 (equal to V1-V2) coupling intervals. At each coupling interval tested within the zone of atrioventricular (A-V) nodal effective refractory period (since anterograde block of A2 was considered mandatory for manifestation of antidromic reentry), responses were assessed after A2 alone (method I), V2 alone (method II), and A2 plus V2 (method III, the complete preexcitation model). The entire pacing protocol was performed at two A-V intervals, short (50 msec) and long (150-180 msec), thereby simulating different proximities between the A pacing site and "accessory pathway" location. Of 47 consecutive unmedicated patients screened for the study protocol, 38 failed to meet minimal prerequisites for possible initiation of antidromic reentry because of failure in 18 (38% of total) to achieve anterograde A-V nodal block of A2, even though 1:1 ventriculoatrial conduction to cycle lengths less than or equal to 500 msec (less than or equal to 400 msec in 12) was present; and poor or absent ventriculoatrial conduction in the others. The nine remaining candidates underwent the full pacing protocol. Antidromic reentry (retrograde atrial response following V2 in method III) was observed in only two cases (4% of total), and both were associated with retrograde His-Purkinje system delays (documented by method II) occurring in tandem with a long A-V interval, thereby allowing for completion of retrograde A-V nodal recovery after penetration by A2. Indeed, such a prolonged recovery time prevented initiation of antidromic reentry in six of the nine patients (proven by intact ventriculoatrial conduction in method II). Retrograde A-V nodal block of V2, independent of A2, prevented an antidromic echo in one case. Findings in our model help to clarify the various factors, including specific anterograde and retrograde A-V nodal properties; anatomic relation between the accessory and normal pathways; and the retrograde His-Purkinje system delays, that must prevail in a concerted fashion to permit the initiation of antidromic reentry during the A1-A2 technique in patients with the WPW syndrome.