Recommendations regarding ibuprofen use in relation to coronavirus disease 2019 (COVID-19) have been conflicting. We examined the risk of severe COVID-19 between ibuprofen-prescribed and non-ibuprofen patients with COVID-19 in a nationwide register-based study of patients with COVID-19 in Denmark between the end of February 2020 and May 16, 2020. Patients with heart failure (n = 208), < 30 years (n = 575), and prescribed other nonsteroidal anti-inflammatory drugs (n = 57) were excluded. Patients with ibuprofen prescription claims between January 1, 2020, and before COVID-19 diagnosis or April 30, 2020 (last available prescription) were compared with patients without ibuprofen prescription claims. Outcome was a 30-day composite of severe COVID-19 diagnosis with acute respiratory syndrome, intensive care unit admission, or death. Absolute risks and average risk ratios comparing outcome for ibuprofen vs. non-ibuprofen patients standardized to the age, sex, and comorbidity distribution of all patients were derived from multivariable Cox regression. Among 4,002 patients, 264 (6.6%) had ibuprofen prescription claims before COVID-19. Age, sex, and comorbidities were comparable between the two study groups. Standardized absolute risks of the composite outcome for ibuprofen-prescribed vs. non-ibuprofen patients were 16.3% (95% confidence interval (CI) 12.1–20.6) vs. 17.0% (95% CI 16.0–18.1), P = 0.74. The standardized average risk ratio for ibuprofen-prescribed vs. non-ibuprofen patients was 0.96 (95% CI 0.72–1.23). Standardized absolute risks of the composite outcome for patients with ibuprofen prescription claims > 14 days before COVID-19 vs. ≤ 14 days of COVID-19 were 17.1% (95% CI 12.3–22.0) vs. 14.3% (95% CI 7.1–23.1). In conclusion, in this nationwide study, there was no significant association between ibuprofen prescription claims and severe COVID-19.