Background: In the pediatric patient, central venous catheterization may be associated with relevant complications. Though, most of them may be prevented by a wise choice of materials, methods, and techniques. Evidence-based insertion bundles for central venous catheterization have been developed in the adult patient, but not in neonates and children. Methods: The Italian Group for Long Term Venous Access Devices (GAVeCeLT) has developed an insertion bundle for central venous catheterization in neonates, infants, and children, which includes seven evidence-based strategies: (1) preprocedural ultrasound evaluation, (2) appropriate aseptic technique, (3) ultrasound guided venipuncture, (4) intraprocedural tip location by non-radiological methods, (5) proper choice of the exit site by tunneling, (6) sutureless securement, and (7) protection of the exit site using glue and transparent membranes. The effectiveness and safety of this bundle has been tested in a prospective study. Results: All neonates, infants and children requiring a non-emergency central line (except for umbilical venous catheters and epicutaneo-cava catheters) were included in the study. Out of 729 central line insertions, there were no immediate complications (no pneumothorax, no arterial puncture, no malposition); the incidence of early and late complications (local ecchymosis, dislodgment, local pain, exit site infection) was 3.7%; in the first 2 weeks after insertion, no catheter-related bacterial infection or catheter-related thrombosis was recorded. Conclusion: The results of this prospective study strongly validate the hypothesis that an insertion bundle is highly effective in optimizing the safety of the maneuver, reducing immediate, early, and late complications.