Background: Distinguishing primary bloodstream infections (BSIs) related to central venous access devices (CVADs) from those that occur through other mechanisms, such as a damaged mucosal barrier, is difficult. Methods: Secondary analysis was conducted on data from patients with CVADs that were collected for a large, randomized trial. Patients were divided into two groups: those who received parenteral nutrition (PN)–containing intravenous lipid emulsion (ILE) and those who did not have PN-containing ILE. This study investigated the influence of PN-containing ILE (ILE PN) on primary BSIs in patients with a CVAD. Results: Of the 807 patients, 180 (22%) received ILE PN. Most (627/807; 73%) were recruited from the hematology and hematopoietic stem cell transplant unit, followed by surgical (90/807; 11%), trauma and burns (61/807; 8%), medical (44/807; 5%), and oncology (23/807; 3%). When primary BSI was differentiated as a central line-associated BSI (CLABSI) or mucosal barrier injury laboratory-confirmed BSI (MBI-LCBI), the incidence of CLABSI was similar in the ILE PN and non–ILE PN groups (15/180 [8%] vs 57/627 [9%]; P = 0.88) and the incidence of MBI-LCBI was significantly different between groups (31/180 [17%] ILE PN vs 41/627 [7%] non–ILE PN; P < 0.01). Conclusion: Our data indicate that twice as many primary BSIs in ILE PN patients are due to MBIs than CVADs. It is important to consider the MBI-LCBI classification, as some CLABSI prevention efforts aimed at CVADs for the ILE PN population may be better directed to gastrointestinal tract protection interventions.