Propofol is one of the first-line sedative-hypnotic agents for critically ill adults requiring mechanical ventilation. Although propofol can elevate triglyceride levels, and the latter is a risk factor for pancreatitis, the association between propofol and acute pancreatitis is unclear. We sought to determine the clinical impact and potential associations between propofol infusion, hypertriglyceridemia, and acute pancreatitis. This is an observational multicenter study of adults (⩾18 yr old) who were admitted to an intensive care unit, who required mechanical ventilation and received continuous propofol infusion for at least 24 hours. The primary outcomes were the frequency of hypertriglyceridemia (>400 mg/dl) and acute pancreatitis. Further analyses were done to determine the clinical impact of elevated triglyceride levels (i.e., sedation changes) and risk factors for pancreatitis development. Of 11,828 patients included, 33.2% ( = 3,922) had triglyceride levels measured, of whom 21.7% ( = 851) had hypertriglyceridemia at 4.5 days (SD = 6.8) after propofol initiation. Of those still requiring sedation, 70.4% ( = 576/818) received alternative sedatives after developing hypertriglyceridemia. Pancreatitis occurred in 1.2% of patients ( = 47/3,922) and was more frequent in those with hypertriglyceridemia (3.2%, 27/851; vs. 0.7%, 20/3,071;  < 0.001). After adjustment for potential confounding variables, each 100 mg/dl increase in triglyceride levels was associated with an 11% increase in risk of pancreatitis. Propofol dose was not associated with pancreatitis development. Acute pancreatitis is uncommon in patients receiving propofol infusion, and it occurs over a wide range of triglyceride levels, indicating a multifactorial pathophysiology. Hypertriglyceridemia frequently prompts the use of alternative sedatives. Further study is needed to determine how to best monitor and treat hypertriglyceridemia in critically ill patients receiving propofol infusion.