Aim: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that has no approved treatment. There are some medications which may be prescribed for COVID-19 patients as investigational treatments. Drug-drug interactions (DDIs) of medications used in treating COVID-19 is an important issue to be studied. Current study aimed to evaluate potential DDIs (pDDIs) and their predictors in hospitalized COVID-19 patients. Methods: A retrospective chart review study was conducted in a tertiary respiratory hospital dedicated for COVID-19 patients. Interacting drug combinations, severity, reliability, mechanism, and clinical management of pDDIs in confirmed COVID-19 cases were identified using the Lexi-Interact database. Logistic regression was applied to assess the correlation between occurrence of severe interactions and probable risk factors. Results: Two hundred and twenty-seven patients’ medical charts were evaluated. About 68% of the patients had at least one comorbidity. The most common comorbidity was hypertension (30.4%), followed by obesity (27.8%) and diabetes (23.8%). At least one major or contraindicated interaction was detected in 37.9% of the patients. Above 50% of the interactions were between lopinavir/ritonavir (protease inhibitor) and commonly prescribed medications (e.g. atorvastatin, alprazolam, salmeterol, and tamsulosin) for management of comorbidities or COVID-19 symptoms. Logistic regression analysis demonstrated that two comorbidities (IHD and CRDs) and ICU admission are significantly associated with occurrence of major or contraindicated pDDIs. Conclusion: The frequency of pDDIs is relatively high in COVID-19 patients. Patients receiving a protease inhibitor and having comorbidity or critical conditions should be monitored carefully in terms of DDIs.