The objective of this study was to assess the risk of central line-associated bloodstream infection (CLABSI) of ultrasound (US)guided cannulation of the brachiocephalic vein (BCV) compared to standard epicutaneous cava catheters (ECCs) in preterm infants. This was a retrospective cohort study in preterm infants with a birth weight of less than 1500 g. Each BCV catheter was matched 1:3 with ECCs according to sex, birth weight, and year of insertion. The main outcome was the CLABSI density rate per 1000 days. Secondary outcomes included CLABSI episodes, CLABSI episodes per infant, and CLABSI/death. A multivariate Cox regression analysis was performed to assess whether the type of catheter (ECC vs. BCV) was associated with CLABSI risk. Ninety-six catheters (21 BCVs and 75 ECCs) in 79 infants were included (993 catheter days). BCV catheters were associated with a reduced CLABSI density rate compared to ECCs (3.05/1000 days vs 21.1/1000 days; p < 0.001). ECCs were associated with increased CLABSI risk compared to BCV catheters in multivariate analysis (hazard ratio 36; (95% CI, 2.5-511); p = 0.008).Conclusion: US-guided supraclavicular cannulation of the BCV was associated with a reduced risk of CLABSI compared to ECCs. This finding deserves further multicenter research. What is Known:• An epicutaneous-cava catheter (ECC) is commonly used in preterm infants for routine care (eg. delivery of nutrition and antibiotics) but this device may not suffice in infants who need high-intensity care (multiple drugs, hemodynamic monitoring, fluid resuscitation etc.). • Ultrasound-guided brachiocephalic vein (BCV) catheterization has shown a high success rate and few immediate complications in neonates and small infants but it has never been compared to standard ECCs. What is New: • When the operator in properly trained, US guided cannulation of the BCV in preterm infants is feasible, safe and may reduce the risk of CLABSI compared to standard ECCs. • This fact may expand the use of BCV catheters in selected high-risk preterm infants who need a large bore venous access.