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IMPORTANCE:. In the ICU, opioids treat pain and improve ventilator tolerance as part of an analgosedation approach. Identifying predictors of opioid consumption during the ICU course might highlight actionable items to reduce opioid consumption. OBJECTIVES:. To identify risk factors for opioid use during a postoperative ICU course. DESIGN, SETTING, AND PARTICIPANTS:. Patients enrolled in the Michigan Genomics Initiative single-center prospective observational cohort study completed baseline preoperative sociodemographic and mental/physical health questionnaires and provided blood samples for genetic analysis. Included patients were 18 years old and older, admitted to ICU postoperatively, and received opioids postoperatively. MAIN OUTCOMES AND MEASURES:. The primary outcome was ICU mean daily oral morphine equivalent (OME) use. The association between OME and phenotypic risk factors and genetic variants previously associated with pain were analyzed through univariable and multivariable linear regression models. RESULTS:. The cohort consisted of 1865 mixed-surgical patients with mean age of 56 years (sd, 15 yr). Preoperative opioid users were more likely to continue to receive opioids throughout their ICU stay than opioid-naive patients. OME (log10 scale) was most strongly associated with ICU mechanical ventilation (β = 0.27; 95% CI, 0.15–0.38; p < 0.0001; effect size 1.85 for receiving > 24 hours of mechanical ventilation), preoperative opioid use (β = 0.22; 95% CI, 0.16–0.29; p < 0.0001; effect size 1.67 for receiving preoperative opioids), major surgery (β = 0.21; 95% CI, 0.12–0.30; p < 0.0001; effect size 1.62 compared with minor surgery), and current/former illicit drug use (β = 0.12; 95% CI, 0.01–0.23; p = 0.04; effect size 1.30 for drug use). Younger age, centralized pain, and longer anesthetic duration were also significantly associated with OME but with smaller effect sizes. Selected genetic variants (FKBP5, COMT, and OPRM1) were not associated with OME use. CONCLUSIONS AND RELEVANCE:. Mechanical ventilation and preoperative opioids were the strongest risk factors for postoperative ICU opioid consumption, whereas psychologic factors and genetic variants were not associated.