•New oral antivirals Paxlovid and Lagevrio can prevent the progression of COVID-19.•Oral antiviral treatment of early-stage COVID-19 poses a risk of significant drug-drug interactions (DDI).•Polypharmacy is frequent in patients at high risk of severe COVID-19.•Danish prescription data show frequent use of drugs prone to interact with Paxlovid.•Guidance for physicians managing DDI with COVID-19 treatment is needed. The oral antiviral drugs nirmatrelvir/ritonavir (NMV/r) and molnupiravir have been approved for early outpatient treatment of COVID-19 to prevent severe disease. Ritonavir, contained in NMV/r, is known to have significant drug-drug interactions (DDI) with several drugs frequently used by the elderly. This communication puts the problem with DDI with oral antiviral COVID-19 treatment into perspective by assessing the percentage of the elderly population at risk of severe COVID-19, using drugs with significant DDI with oral antivirals. We estimated the size of the Danish population at risk of significant DDI with antiviral COVID-19 treatment using the number of claimed prescriptions for drugs predicted to interact with NMV/r in Denmark in 2020. Danish prescription data demonstrate the extensive use of drugs likely to interact with NMV/r. Anticoagulants contraindicated during NMV/r treatment were used by 20% of people ≥65 years and 30% of people ≥80 years. Statins that must be paused during NMV/r treatment were used by 15-18%. More than one in five used either analgesics, calcium channel blockers, or digoxin. There is major potential for significant DDI with NMV/r in the elderly population at risk of severe COVID-19 disease. This calls for clear guidance for prescribers to ensure patient safety and treatment success.