Background: Central venous catheters (CVCs) are essential in intensive care units (ICUs) for monitoring and administering treatments; however, catheter-related bloodstream infections (CRBSIs) are significant complications, leading to severe outcomes and increased healthcare costs. The objective of this study was to evaluate the effectiveness of a simple and inexpensive impregnated dressing (intervention) compared to a non-impregnated dressing in reducing catheter-related infections among critically ill patients using vancomycin and chlorhexidine. Methods: This was a randomized, double-blind, controlled clinical trial in a university hospital in Brazil with 207 beds from June 2022 to October 2023. Patients over 18 years old admitted to the ICU and needing a CVC for a period exceeding 72 h were included. A CVC inserted outside the ICU and the need for two CVCs in the same patient simultaneously were exclusion criteria. One group received an impregnated dressing (intervention) compared to the other group, which received a standard dressing (comparator). The incidence of CRBSIs and the microbiological outcomes were evaluated. The primary endpoint was CRBSI. Results: The clinical trial included 516 patients randomized to receive either the new antimicrobial dressing or a control dressing. The dressing significantly reduced CVC colonization but not CRBSI rates. Conclusions: This new dressing provides enhanced antimicrobial protection but does not decrease CRBSI incidence. Future studies should further explore the cost-effectiveness and long-term benefits of this approach.