Central venous line (CVL) dysfunction (mainly from thrombotic occlusion) is a frequent, but relatively less-studied complication compared with infection and thromboembolism (TE). In adults with cancer, TE results in poor outcome. We evaluated the impact of CVL-dysfunction and TE on overall survival (OS) and event-free survival (EFS) in children with noncentral nervous system cancer (n=358). CVL-dysfunction was defined as persistent or recurrent difficulty of blood draw and/or infusion. Event was defined as cancer relapse, second malignancy, or death due to any cause. OS and EFS were estimated using Kaplan-Meier method and survival curves compared using log-rank test. Hazard ratios (HR) were calculated using the Weibull regression model. Diagnosis of TE (n=43, 12%) had no effect on the OS and EFS. Children with CVL-dysfunction (n=74, 21%) had shorter 5- and 10-year EFS compared with children without CVL-dysfunction (P=0.029 and P=0.027). Multiple regression analyses, adjusting for age, sex, diagnostic era, TE, and cancer type identified CVL-dysfunction as an independent determinant of 5-year OS (HR 1.87; 95% confidence interval, 1.02-3.42; P=0.043) and EFS (HR 1.96; 95% confidence interval, 1.23-3.41; P=0.018). Although the etiology of adverse impact of CVL-dysfunction on survival is unknown, its prevention and prompt treatment may improve outcome from cancer in children. Further prospective studies are recommended.