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Background: Central venous access devices (CVADs) are used for parenteral nutrition (PN) delivery. We systematically reviewed research-based publications that reported comparative rates of catheter-related bloodstream infection (CRBSI) in patients with CVADs who received PN vs those who did not receive PN therapy. Materials and Methods: The literature search included the Cochrane Library, MEDLINE, CINAHL, and PubMed up to July 14, 2015, to identity studies that compared patients with a CVAD who did and did not have PN therapy. Results: Eleven observational studies were identified, comprising 2854 participants with 6287 CVADs. Six studies produced significant results in favor of non-PN, 4 studies showed no evidence of a difference between PN and non-PN, and 1 study produced significant results in favor of PN when analyzed per patient with multiple CVADs. Incidence ranged from 0 to 6.6 CRBSIs per 1000 CVAD days in the PN patients and 0.39 to 3.6 CRBSIs per 1000 CVAD days in the non-PN patients. The Cochrane risk of bias assessment tool for nonrandomized studies of interventions was used. Eight studies were rated as moderate risk of bias, 2 as serious, and 1 as critical. Conclusion: The data presented in this systematic review are not sufficient to establish whether patients receiving PN are more at risk of developing CRBSI than those who do not. Future PN studies needs to adjust for baseline imbalances and improve quality and reporting.