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Background: Several medications have been proposed to manage COVID-19, with controversial data regarding their clinical benefits. We aimed to investigate the clinical efficacy of using remdesivir (RDV) with and without tocilizumab (TCZ) and standard therapy in treating severe COVID-19., Methods: This retrospective cohort study was conducted in a Jordanian tertiary hospital (September 26th, 2020 - August 28th, 2021) and included adult COVID-19 patients requiring oxygen support. Patients were categorized into three groups based on treatment: TCZ+RDV and standard therapy; RDV and standard therapy; and standard therapy alone, which included dexamethasone, vitamins, anticoagulants, and ceftriaxone., Results: Of 1,556 screened, 1,244 patients (mean age 62.33, 60.8% men) were included. Distribution was 106 in TCZ+RDV, 520 in RDV, and 618 in standard therapy. No significant differences were observed in age, gender, or BMI. Mortality was lowest in TCZ+RDV (32.1%), followed by RDV (40.6%) and standard therapy (47.1%) (p=0.005). Among ICU patients, TCZ+RDV showed significantly lower mortality (51.1%) compared to RDV (75%) and standard therapy (85.8%) (p<0.001). The ICU stays and invasive mandatory ventilation (IMV) durations were significantly shorter with TCZ+RDV (4.30 and 2.69 days, respectively) compared to RDV (7.61 and 4.52 days) and standard therapy (7.98 and 5.32 days) (p<0.001 for ICU stays, p=0.025 for IMV durations)., Conclusions: Combining TCZ, RDV, and dexamethasone shows promise in reducing mortality and ICU/IMV duration for severe COVID-19., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Institutional Review Board (IRB) at Jordan University of Science and Technology (JUST) issued approval 27/137/2021. This study was conducted following the 1975 Helsinki Declaration, as revised in 2008, and later amendments or comparable ethical standards. The patients’ information was kept confidential, and the data analysis was conducted on the de-identified database. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Al-Mistarehi et al.)