Aims: Lopinavir (LPV) and ritonavir (RTV) is using as combination therapy for combating COVID-19 in considerable proportion of patients. However, the potential clinically significant life-threatening drug-drug interactions (DDIs) of this combination antiviral therapy used in the treatment of COVID-19 patients is not systematically reviewed. It was aimed to identify severe DDI pairs of LPV/RTV from international resources predicted to cause life-threatening adverse drug reactions (ADRs) and cross-compared between the resources. Methods: Severe DDI pairs predicted to cause life-threatening ADRs were identified from the FDA and Liverpool COVID-19 prescribing information of LPV/RTV. Results: In total, 62 severe DDI pairs were identified from the FDA and Liverpool COVID-19 drug interactions resources predicted to cause life-threatening ADRs in patients with COVID-19. Of these, seven unique DDI pairs were identified from the FDA only whereas 45 unique DDI pairs were identified from the Liverpool COVID-19 drug interactions resource. Of interest, only 10 DDI pairs were recognized by both of these drug interaction resources. Conclusion: Clinicians should not entirely rely on any individual DDI resource for checking life threatening ADRs of LPV/RTV in patients with COVID-19 since there were discrepancies in enlisting contraindicated drugs.