BACKGROUND: Few studies have been conducted on long-term survival of children with major birth defects because of a lack of longitudinal birth defects surveillance data. The objective of this study was to conduct a 25-year survival analysis among children in New York born with major defects by survival age, birth defect category, and other possible contributing factors. METHODS: A cohort was constructed containing children born in 1983 to 2006 with selected major birth defects. Deaths among the study cohort were identified by matching the children to their death certificates. The survival probability was estimated by Kaplan-Meier methods. Cox proportional hazards regression was used to examine the effect of the risk factors on survival. RESULTS: A total of 9112 deaths were identified among 57,002 live births with selected birth defects between 1983 and 2006. The overall 25-year survival probability of the study cohort was 82.51% (95% confidence interval, 82.11–82.89%). The estimated survival probability was comparable to that reported from previous studies regarding individual defects including spina bifida, encephalocele, atrioventricular septal defects, tracheoesophageal fistula and esophageal atresia or stenosis, renal agenesis or dysgenesis, lower limb reduction, diaphragmatic hernia, abdominal wall defects, and Down syndrome. Sex, low birth weight for gestational age, existence of multiple birth defects (nonisolated), and maternal age and nativity were identified as risk factors. CONCLUSION: Using the statewide, population-based birth defects surveillance data in New York State, the survival experience of the study cohort was examined across all survival time periods by individual birth defect of interest. Several risk factors that affect survival were identified. Birth Defects Research (Part A), 2011. © 2011 Wiley Periodicals, Inc.