We aimed to investigate whether comorbid musculoskeletal disorders (MSD)s and pain medication use was associated with in-hospital mortality among patients with coronavirus disease 2019 (COVID-19). Adult patients (>/=20 years old) with a positive COVID-19 diagnosis until 5 June 2020 were included in this study, based on the National Health Insurance COVID-19 database in South Korea. MSDs included osteoarthritis, neck pain, lower back pain, rheumatoid arthritis, and others, while pain medication included paracetamol, gabapentin, pregabalin, glucocorticoid, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids (strong and weak opioids), and benzodiazepine. Primary endpoint was in-hospital mortality. A total of 7713 patients with COVID-19 were included, and in-hospital mortality was observed in 248 (3.2%) patients. In multivariate logistic regression analysis, no MSDs (p > 0.05) were significantly associated with in-hospital mortality. However, in-hospital mortality was 12.73 times higher in users of strong opioids (odds ratio: 12.73, 95% confidence interval: 2.44-16.64; p = 0.002), while use of paracetamol (p = 0.973), gabapentin or pregabalin (p = 0.424), glucocorticoid (p = 0.673), NSAIDs (p = 0.979), weak opioids (p = 0.876), and benzodiazepine (p = 0.324) was not associated with in-hospital mortality. In South Korea, underlying MSDs were not associated with increased in-hospital mortality among patients with COVID-19. However, use of strong opioids was significantly associated with increased in-hospital mortality among the patients.