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Celecoxib, a nonsteroidal anti-inflammatory agent, was found to be an effective add-on treatment for unipolar and bipolar depression. We investigated the potential beneficial effect of celecoxib monotherapy on depressive symptoms after Coronavirus disease (COVID-19). This was a randomized, double-blind, placebo-controlled clinical trial investigating the therapeutic effects of celecoxib monotherapy in patients with moderate depressive symptoms following COVID-19 infection. Patients were randomized to receive either a celecoxib capsule (100 mg) twice daily or a placebo capsule twice daily for 6 weeks. Participants were assessed with the Hamilton Depression Rating Scale (HDRS) and the side effect checklist at baseline and weeks 3 and 6. A total of 62 patients were included. GLM repeated-measures showed a significant effect of time × treatment (F = 12.95, df = 1.98, p < 0.001) for celecoxib, suggesting superior improvement of depressive symptoms in celecoxib compared to placebo from baseline to the study endpoint. HDRS scores in the celecoxib group showed a greater decline from baseline to both week 3 (t = 4.12, p < 0.001, Cohen's d = 1.10) and week 6 (t = 4.76, p < 0.001, Cohen's d = 1.27), compared to the placebo group. Rate of response to treatment (70% vs 9%, p < 0.001) and remission (67% vs 0%, p < 0.001) was significantly higher in celecoxib compared to the placebo group at week 6. Adverse event frequencies were not significantly different between the two groups. We demonstrated that treatment with celecoxib significantly improved depression scores of patients with depressive symptoms following COVID-19 infection. Further trials with larger sample sizes and longer study periods should assess our findings before any suggestion for clinical use. The trial was prospectively registered at the Iranian registry of clinical trials (www.irct.ir ; registration number: IRCT20090117001556N142). • COVID-19 patients are affected by depressive symptoms after acute phase. • Celecoxib significantly improved depression scores of patients with post-COVID-19 • Rate of response to treatment and remission was higher in the celecoxib group • Treatment with celecoxib was safe. [ABSTRACT FROM AUTHOR]