Objectives: While the safety of non-steroidal anti-inflammatory drugs in COVID-19 has been questioned, they may be beneficial given the hyper-inflammatory immune response associated with severe disease. We aimed to assess the safety and potential efficacy of cyclooxygenase-2 (COX-2) selective inhibitors in high-risk patients. Methods: Retrospective study of patients with COVID-19 pneumonia and aged >/= 50 years who were admitted to hospital. Adverse outcomes analysed included supplemental oxygen use, intensive care unit admission, mechanical ventilation and mortality, with the primary endpoint a composite of any of these. Plasma levels of inflammatory cytokines and chemokines were measured in a subset. Results: Twenty-two of 168 (13.1%) in the cohort received COX-2 inhibitors [median duration 3 days, interquartile range (IQR) 3-4.25]. Median age was 61 (IQR 55-67.75), 44.6% were female, and 72.6% had at least one comorbidity. A lower proportion of patients receiving COX-2 inhibitors met the primary endpoint: 4 (18.2%) versus 57 (39.0%), P = 0.062. This difference was less pronounced after adjusting for baseline difference in age, gender and comorbidities in a multivariate logistic regression model [adjusted odds ratio (AOR) 0.45, 95% CI 0.14-1.46]. The level of interleukin-6 declined after treatment in five of six (83.3%) treatment group patients [compared to 15 of 28 (53.6%) in the control group] with a greater reduction in absolute IL-6 levels (P-value = 0.025). Conclusion: Treatment with COX-2 inhibitors was not associated with an increase in adverse outcomes. Its potential for therapeutic use as an immune modulator warrants further evaluation in a large randomised controlled trial.