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Background: Recent studies have found a link between the usage of selective serotonin reuptake inhibitors (SSRIs) and a lower mortality rate in COVID-19 cases. Objective: The goal of current research was evaluating the effectiveness of SSRI drugs on improvement of COVID-19 patients. Methods: This prospective case-control study, compared SSRI-treated patients with matched control patients not treated with SSRIs at Masih Daneshvari Hospital on a population of 350 patients diagnosed with COVID-19 from March 15th 2021 to March 16th 2022. Results: ICU admission rates were significantly more in the control group than in the case group (44.8% vs. 25.9%; p-value=0.0002; Odds Ratio (OR)= 2.32). Intubation was reported for more cases in the control group than the case group (26.7% vs. 11.4%; p-value=0.0002; OR=2.84). Mortality rate was found to be significantly more in the control group than the case group (23.0% vs. 10.8%; p-value=0.0002; OR=2.46). Furthermore, the subgroup analyses on Fluvoxamine and Sertraline showed that Hospitalization period, ICU admission rates, and intubation were all reported to be significantly smaller in each case subgroups as against the control group. Conclusion: Our assessments underlined the potential efficacy of SSRIs in improving COVID-19 patients’ prognosis, since the use of SSRIs were shown to be associated with shorter hospital stay and ICU stay, lower ICU admission rates and intubation rates, and ultimately decreased mortality rates.

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