Chronic disease and opioid-related hospitalizations in the United States are increasing. We analyzed nationally representative data on patients aged 18 years or older from the 2011-2015 National Inpatient Sample to assess the association between opioid-related hospitalization and chronic diseases. We found that most patients with opioid-related hospitalization were white, aged 35-54 years, in urban hospitals, and had 2 or more comorbid conditions. Patients with 2 or more chronic conditions accounted for more than 90% of opioid-related hospitalizations in all years. The results suggest a need for targeted interventions to prevent opioid misuse in patients with multiple chronic conditions.