Opioid use is a topic of growing concern among patients with nonalcoholic fatty liver disease (NAFLD). Given safety concerns of opioids, proactively identifying subgroups of patients with an increased probability of opioid use may encourage practitioners to recommend alternative therapies for pain, thus reducing the likelihood of opioid misuse. This work assessed the prevalence and patient characteristics associated with opioid use in a real-world cohort of patients with NAFLD. TARGET-NASH, an observational study of participants at 55 academic and community sites in the United States, includes patients with NAFLD defined by pragmatic case definitions. Opioid use was defined as any documented opioid prescriptions in the year prior to enrollment. The association between patient characteristics and the odds of opioid use were modeled with stepwise multivariable logistic regression and tree ensemble methods (Classification and regression tree/Boosted Tree). The cohort included 3,474 adult patients with NAFLD including 18.0% with documented opioid use. Variables associated with opioid use included presence of cirrhosis (OR 1.51, 95% CI 1.16-1.98), BMI ≥32 kg/m2 (OR 1.29, 95% CI 1.05-1.59), depression (OR 1.87, 95% CI 1.50-2.33), and anxiety (OR 1.59, 95% CI 1.27-1.98). In the boosted tree analysis, history of back pain, depression, and fibromyalgia had the greatest relative importance in predicting opioid use. Prescription opioids were used in nearly 1 of 5 patients with NAFLD. Given the safety concerns of opioids in patients with NAFLD, alternative therapies including low-dose acetaminophen and nonpharmacologic treatments should be considered for these patients.