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Objectives: To evaluate the effectiveness of needle-free connectors to maintain Central Venous Catheter—CVC patency. Background: Loss of patency is a common complication associated with CVC. For patients, this can be stressful and painful, and can result in a delay in infusion therapy. Pressure-activated anti-reflux needle-free connectors are one of the most modern devices; however, no studies have compared this connector with the open-system three-way stopcock in terms of the incidence of CVC occlusion. Methods: This study is a prospective before and after intervention study. From March to August 2018, an observation phase was conducted with the three-way stopcock as the standard central venous catheter hub and closure system (phase 1). After implementation of needle-free connectors (phase 2), post-intervention observations were made from September 2019 to January 2020 (phase 3). Results: Of 199 CVCs analyzed, 41.2% (40/97) occluded in at least one lumen in the first phase, and 13.7% (14/102) occluded after introducing the technological device, absolute risk reduction 27.5% (95% confidence interval 15.6%–39.4%). The lumens supported by needle-free connectors showed a higher probability of maintaining patency compared with three-way stopcocks. No differences were observed in the rate of infection. Conclusions: Pressure-activated anti-reflux needle-free connectors are effective and safe devices suitable for the management of vascular access in cardiac patient care. Staff training, even on apparently simple devices, is essential to avoid the risk of infection.