Improved survival of children with cancer has been accompanied by multiple treatment-related complications. However, most studies in survivors of childhood cancer focused on only 1 late effect. To assess the total burden of adverse health outcomes (clinical or subclinical disorders "adverse events") following childhood cancer in a large cohort of childhood cancer survivors with long-term and complete medical follow-up. Retrospective cohort study of 1362 five-year survivors of childhood cancer treated in a single institution in the Netherlands between 1966 and 1996. All survivors were invited to a late-effects clinic for medical assessment of adverse events. Adverse events occurring before January 2004 were graded for severity in a standardized manner. Treatment-specific prevalence of adverse events (according to severity) at end of follow-up and relative risk of high or severe burden of disease (> or =2 severe or > or =1 life-threatening or disabling adverse events) associated with various treatments. Medical follow-up was complete for 94.3% of survivors (median follow-up, 17.0 years). The median attained age at end of follow-up was 24.4 years. Almost 75% of survivors had 1 or more adverse events, and 24.6% had 5 or more adverse events. Furthermore, 40% of survivors had at least 1 severe or life-threatening or disabling adverse event. A high or severe burden of adverse events was observed in 55% of survivors who received radiotherapy only and 15% of survivors treated with chemotherapy only, compared with 25% of survivors who had surgery only (adjusted relative risks, 2.18 95% confidence interval, 1.62-2.95 and 0.65 95% confidence interval, 0.46-0.90, respectively). A high or severe burden of adverse events was most often observed in survivors of bone tumors (64%) and least often in survivors of leukemia or Wilms tumor (12% each). In young adulthood, a substantial proportion of childhood cancer survivors already has a high or severe burden of disease, particularly after radiotherapy. This underscores the need for lifelong risk-stratified medical surveillance of childhood cancer survivors.