BACKGROUND: Hepatic encephalopathy (HE) is a common complication of cirrhosis associated with decreased quality of life and increased mortality. Opioids are commonly used to treat pain in patients with cirrhosis and may increase the risk of hepatic encephalopathy. In a population of patients with cirrhosis and no prior decompensation events, we aimed to assess whether opioids were associated with (1) HE and (2) other decompensation events (variceal bleed, hepatocellular carcinoma, ascites). METHODS: We used the IMS PharMetrics database, which includes claims from >70 million privately-insured people in the United States, to identify patients aged 18–64 years with cirrhosis diagnosed from 1/1/2007 to 10/1/2015 based on the presence of two ICD-9 codes (571.2 or 571.5) on separate dates. We excluded patients with any decompensation event (defined by ICD codes, procedures and medications) from 1 year before cirrhosis diagnosis to 3 months after cirrhosis diagnosis. Opioid exposure was assessed over a 6 month period after cirrhosis diagnosis. Exposure to gabapentin and statins were assessed as positive and negative controls, respectively, to assure internal validity of the database. Our outcomes (HE and other decompensation events) were assessed in the subsequent 6 months (i.e. 6 months-1 year after cirrhosis diagnosis). We performed multivariable logistic regression, adjusting for Charlson comorbidity index, cirrhosis etiology, sex and age to assess the association between opioid, gabapentin and statin prescription and decompensation events. RESULTS: Of all patients with compensated cirrhosis (n = 7,580), 30.3%, 2.6% and 10.0% received opioid, gabapentin and statin prescriptions within 6 months after cirrhosis diagnosis. In the subsequent 6 months, 3.1% developed HE and its diagnosis was more common among those with prescriptions for opioids than those without (4.2% vs 2.6%, P < 0.001) but not associated with prescriptions for gabapentin (4.1% vs 3.0%, P = 0.397) or statins (2.8% vs 3.1%, P = 0.738). In the multivariable model, a higher odds of HE was seen in patients with opioid prescriptions (OR 1.69, 95% CI 1.29–2.22), but not gabapentin (OR 1.34, 95% CI 0.65–2.78) or statin prescriptions (OR 0.86, 95% CI 0.54–1.36). In multivariable models, opioids were not significantly associated with other decompensation events. CONCLUSION: In this nationwide cohort of privately-insured patients with cirrhosis, opioid prescriptions were common and significantly associated with higher odds of developing HE. Positive and negative controls performed as expected, supporting the validity of the data. Given their potential risks, opioids should be minimized in patients with cirrhosis, even in the absence of prior decompensation events.