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Rationale: Propofol is a first-line sedative agent in the intensive care unit (ICU) but may be associated with hypertriglyceridemia and pancreatitis. To date, the relationship between propofol-induced hypertriglyceridemia and pancreatitis, as well as clinician responses to propofol-induced hypertriglyceridemia, have not been comprehensively studied. Objectives: To assess the incidence of hypertriglyceridemia and pancreatitis in patients receiving continuous propofol infusions in the ICU and to describe the association between hypertriglyceridemia and the use of nonpropofol continuous sedative infusions. Methods: This was a retrospective observational cohort study conducted at three urban academic hospitals within a single health system. Findings were additionally validated using the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database containing data from a separate tertiary care hospital. Mechanically ventilated adult patients who received a continuous propofol infusion between 2016 and 2021 were included. The primary exposure was serum triglyceride concentration, and hypertriglyceridemia was defined as a triglyceride concentration greater than 400 mg/dl. Outcomes included new-onset pancreatitis as well as receipt of midazolam, dexmedetomidine, or ketamine after the triglyceride measurement. The incidence of pancreatitis was compared between groups using a Fisher's Exact test. Multivariable logistic regression was used to assess the association between dichotomized triglyceride concentration and alternative sedative use. Results: In the primary cohort of 7,037 patients, 1,724 (24.5%) had one or more triglyceride concentration measured. Of these, 1,365 (79.2%) had a maximum concentration of less than 400 mg/dl, and 359 (20.8%) had a maximum concentration of greater than 400 mg/dl. Compared with patients with low triglyceride concentrations, patients with high triglyceride concentrations were more likely to receive a continuous infusion of midazolam (37.0% vs. 16.4%; adjusted odds ratio [aOR], 3.1; 95% confidence interval [CI], 2.2-4.4; P  < 0.01), ketamine (22.8% vs. 6.9%; aOR, 3.5; 95% CI, 2.3-5.3; P  < 0.01), and dexmedetomidine (57.7% vs. 46.6%; aOR, 1.5; 95% CI, 1.1-2.0; P  < 0.01). Rates of midazolam infusion increased as triglyceride concentrations exceeded 500 mg/dl. Forty-four (0.6%) patients developed pancreatitis after propofol initiation, of which 4 (9.1%) were considered related to propofol-associated hypertriglyceridemia. Findings were similar in the MIMIC-IV cohort. Conclusions: Propofol-associated hypertriglyceridemia is relatively common in mechanically ventilated ICU patients who have triglycerides measured. Pancreatitis related to propofol-associated hypertriglyceridemia is rare. Patients who develop hypertriglyceridemia while receiving propofol are more likely to receive continuous infusions of other sedatives.