Abstract Objective To examine factors related to the use of opioids as an early treatment option for knee OA patients Methods Using the Korean nationwide claim database, we selected knee OA patients between 2013 and 2015. Among them, patients without any claim of knee OA for 2 years before the index date were included as our study population. We analyzed their first claim for prescriptions, including tramadol and stronger opioids, at the index date of each patient. Using a multinomial model, we identified factors associated with the early use of tramadol and stronger opioids in knee OA patients. Results Among a total of 2,857,999 knee OA patients, 12.2% (n = 348,516) were treated with opioids as their first treatment. However, the prevalence of stronger opioid use was only 0.07% (n = 1972). Male sex (OR 1.28 in tramadol, OR 1.13 in stronger opioids) and comorbidities with depression (OR 1.05, 1.46), low back pain (OR 1.13, 1.30), intervertebral disc disorder (OR 1.11, 1.40), and spinal stenosis (OR 1.27, 1.55) were the factors for the early use of tramadol or stronger opioids in knee OA patients. Patients in a tertiary referral hospital tended to use tramadol or stronger opioids than those in clinics (OR 1.04, 56.63, respectively). Conclusion In Korea, 12.2% of knee OA patients were treated with opioids as an early treatment, and tramadol was used more commonly than stronger opioids. Male sex and having comorbidities such as depression or musculoskeletal disease are patient factors associated with the early use of opioids in knee OA patients.