Background <p>The necessity of this study stems from the lack of comparative evidence on the outcomes of central venous catheterization via the open internal jugular and ultrasound-guided subclavian approaches in low-weight pediatric patients. Its innovation lies in the simultaneous evaluation of both primary and secondary outcomes of these two techniques in this vulnerable population.</p> Methods <p>This prospective randomized clinical trial at Mardani Azar Children’s Hospital (winter 2022–2023) included 92 pediatric patients under five kilograms weight, randomly assigned to either open internal jugular or ultrasound-guided subclavian vein catheterization (46 per group). Procedural success and major complications—such as pneumothorax, arterial cannulation, ectopic catheter placement, infection, and thrombosis—were evaluated intraoperatively and during a two-weeks follow-up using imaging and clinical assessment.</p> Results <p>The mean catheter placement time was significantly longer in the jugular group than in the subclavian group (41.19 ± 13.8 vs. 33.15 ± 12.12&#xa0;min; <i>P</i> = 0.04). No cases of pneumothorax, hemothorax, bleeding, arrhythmia, occlusion, infection, or death occurred in either group. Hematoma developed only in the jugular group (6 vs. 0; <i>P</i> = 0.02), and all cases were associated with a procedure duration greater than 35&#xa0;min (<i>P</i> = 0.041). In the subclavian group, all failures (<i>n</i> = 4) and upper limb edema (<i>n</i> = 3) occurred exclusively in patients under 2.5&#xa0;kg, with both outcomes significantly linked to lower body weight (<i>P</i> = 0.03 and <i>P</i> = 0.014, respectively). Other complications showed no significant differences between groups.</p> Conclusion <p>Both approaches were generally safe, with no major adverse events observed in either group. Ultrasound-guided subclavian access was associated with a shorter procedure time, whereas hematoma occurred only in the jugular group and catheterization failure and upper-limb edema were seen only in low-weight infants in the subclavian group. However, because access site and technique were evaluated together, their independent effects could not be determined. In addition, the findings in infants weighing &lt; 2.5&#xa0;kg were based on few events and should be considered hypothesis-generating rather than definitive.</p> Trial registration <p>This clinical trial was registered in the Iranian Registry of Clinical Trials (IRCT) with the code IRCT20230901059317N1(Registration date: <b>2024-02-16)</b>.</p>