Background: Although central venous catheters (CVCs) are essential to pediatric cancer care, complications are common (eg, occlusion, central line–associated bloodstream infection [CLABSI]). Parenteral nutrition (PN) and external CVCs are associated with an increased complication risk, but their interaction is unknown. Methods: A retrospective matched cohort study of pediatric oncology patients who received PN through subcutaneous ports or external CVCs. Complication rates were compared between CVC types during PN and non-PN periods (log-negative binomial model). Results: Risk of CLABSI was higher during PN for children with ports (relative risk [RR] = 39.6; 95% confidence interval, 5.0–309) or external CVCs (RR = 2.9; 95% confidence interval, 1.1–7.4). This increased risk during PN was greater for ports than for external CVCs (ratio of relative risks = 13.6). Occlusion risk was higher during PN in both groups (RR = 10.0 for ports; RR = 2.0 for external CVCs), and the increase was significantly greater in ports (ratio of relative risks, 4.9). Overall, complication rates for ports were much lower than for external CVCs during the non-PN period but similar during the PN period. Conclusion: Children with cancer who receive PN have increased risk of CLABSI and occlusion. The risk increase is greatest in children with ports: a 40- and 10-fold increase in infection risk and occlusion, respectively, resulting in similar complication rates during PN regardless of CVC type and negating the usual benefits of ports. Children with cancer who will require PN should have primary insertion of external CVCs where possible.