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Introduction: IV lipid emulsions (LE) are integral components of parenteral nutrition (PN) that provide essential fatty acids, linoleic ace and alpha-linolenic acid. Olive oil-based (OO) LE contains less linoleic acid compared to soybean-oil (SB), making it potentially advantageous in critical illness, infection, and liver injury. Recommendations regarding optimal LE formulation are lacking. This study aimed to compare clinical outcomes in PN containing OO-based versus SB-based LE. Methods: This single-center, retrospective, cohort study included adult hospitalized patients who received PN containing OO-based or SB-based LE. Patients were excluded if received PN prior to hospitalization, duration of PN < 3 days, receipt of both LE, cirrhosis, baseline serum bilirubin > 2 mg/dL, or baseline serum triglycerides > 400 mg/dL. The primary endpoint was rate of PN-associated liver disease (PN-ALD), defined as total bilirubin > 2 mg/dL and/or aspartate aminotransferase (AST), alanine transaminase (ALT), or alkaline phosphatase > 1.5 times upper limit of normal. Secondary outcomes included incidence of culture-proven bloodstream infection, hypertriglyceridemia, and hospital length of stay (LOS). Nominal data was analyzed utilizing Chi-square or Fisher’s exact. Continuous data was analyzed utilizing Student’s t-test or Wilcoxon Rank Sum. Results: A total of 100 patients were included in each group. Most patients received PN for ileus or small bowel obstruction for median duration of 8 (SB-based) vs. 9 days (OO-based). Rates of ICU admission (68 vs. 66) and mortality (13 vs. 8) were similar between OO-based vs. SB-based, respectively. PN-ALD occurred in 35 patients in the OO-based group compared to 28 in the SO-based group (35 % vs. 28%; P = 0.29). There was no difference in hypertriglyceridemia (60 vs. 54), culture proven bloodstream infection (5 vs. 4), ICU LOS (10 vs. 8 days), or hospital LOS (21 vs. 19 days) between OO-based vs. SB-based LE, respectively. Conclusions: Among hospitalized patients receiving PN, there was no difference in PN-ALD when comparing OO-based vs. SO-based LE. Moreover, no difference in hypertriglyceridemia, LOS, or hospital-acquired bloodstream infections was observed between groups. Study findings may be explained by confounding medications, critical illness, or shorter durations of PN.