Venous thromboembolic events (VTEs) in children are associated with central venous lines (CVLs). The study objective was to assess whether CVL location and insertion technique are associated with the incidence of VTE in children. We hypothesized that VTE would be more frequent with (1) CVL location on the left body side, (2) CVL location in the subclavian vein rather than the jugular vein, and (3) CVL insertion by percutaneous technique rather than venous cut-down. This was a prospective, multicenter cohort study in children with acute lymphoblastic leukemia who had a CVL placed in the upper venous system during induction chemotherapy. Characteristics of CVL were documented prospectively. All children had outcome assessment for VTE by objective radiographic tests, including bilateral venography, ultrasound, echocardiography, and cranial magnetic resonance imaging. Among 85 children, 29 (34%) had VTE; 28 VTEs appeared in the upper venous system, and 1 was sinovenous thrombosis. Left-sided CVL (odds ratio [OR], 2.5; 95% confidence interval, 1.0-6.4; P = .048), subclavian CVL (OR, 3.1; 95% CI, 1.2-8.5; P = .025), and percutaneous CVL insertion (OR, 3.5; 95% CI, 1.3-9.2; P = .011) were associated with an increased incidence of VTE. Interaction occurred between CVL vein location and insertion technique. Subclavian vein CVL inserted percutaneously had an increased incidence (54%) of VTE compared with any other combination (P = .07). For CVL in the upper venous system, CVL placement on the right side and in the jugular vein may reduce the risk for CVL-related VTE. If subclavian vein placement is necessary, CVL insertion by venous cut-down appears preferable over percutaneous insertion.