Wolff-Parkinson-White (WPW) syndrome carries a risk for symptomatic arrhythmias and sudden death. The aim of this study was to examine the natural history of patients with Wolff-Parkinson-White syndrome diagnosed in childhood followed longitudinally at a single institution. The study population consisted of 446 patients. The median age of diagnosis was 7 years, and 61% were male. Associated heart disease was present in 40 patients (9%). Modes of presentation included supraventricular tachycardia (38%), palpitations (22%), chest pain (5%), syncope (4%), atrial fibrillation (0.4%), sudden death (0.2%), and incidental findings (26%); data were unavailable in 4%. During the study period, a total of 243 patients (54%) had supraventricular tachycardia, and 7 patients (1.6%) had atrial fibrillation. Of patients who presented at ≤3 months of age, 35% had resolution of manifest preexcitation compared with 5.8% who presented at >3 months of age (p <0.0001). There were 6 sudden deaths (1.3%), with an incidence of 2.8 per 1,000 patient-years. Two of these patients had structurally normal hearts (incidence 1.1 per 1,000 patient-years). Four of these patients had associated heart disease (incidence 27 per 1,000 patient-years) (p <0.01). In conclusion, in a large population of patients with Wolff-Parkinson-White syndrome diagnosed in childhood, 64% had symptoms at presentation, and an additional 20% developed symptoms during follow-up. There were 6 sudden deaths (1.3%), with an overall incidence of 1.1 per 1,000 patient-years in patients with structurally normal hearts and 27 per 1,000 patient-years in patients with associated heart disease. Copyright © 2013 Elsevier Inc. All rights reserved.