The aims of this study were to assess the incidence and risk factors of major central venous catheter (CVC)-related complications in a large cohort of children affected by oncological, hematological, or immunological diseases in a 7-year prospective observational study at a single center. Nine hundred fifteen CVCs were inserted in 748 children for a total period of 307,846 CVC-days. Overall, 298 complications were documented with a complication rate of 0.97/1,000 CVC-days: 105 mechanical complications (dislocations 0.30/1,000 CVC-days, ruptures 0.04/1,000 CVC-days), 174 infections (bloodstream infections 0.46/1,000 CVC-days, tunnel infections 0.10/1,000 CVC-days), and 19 thrombosis (0.06/1,000 CVC-days). Significant risk factors were: diagnosis of acute lymphoblastic leukemia (ALL) and age <or=3 years for dislocations; nonmalignant disease for ruptures; ALL for thrombosis; double-lumen and partially implanted CVCs for bloodstream infections; age <or=3 years for tunnel infections. In conclusion, the rate of CVC-related complications in children was lower than that usually reported.