Background Nirmatrelvir/ritonavir is recommended for high-risk patients with COVID-19 to reduce disease progression and mortality. Ritonavir significantly increases the bioavailability of nirmatrelvir and is the most potent irreversible cytochrome P 450 3A4 inhibitor in clinical use, resulting in a substantial risk for drug-drug interactions (DDI). We aimed to analyze the incidence of potential DDI (pDDI) in critically ill patients with SARS-CoV-2 infection. 7.2 Methods This is a retrospective single-center study in a quaternary care center in Northern Germany. We reviewed electronic health records for demographic characteristics, comorbid conditions, and medication history. The pre-existing comedication was screened for pDDI with nirmatrelvir/ritonavir using publicly available databases. Binary logistic regression was used to identify patient characteristics associated with pDDI. 7.3 Results Of 500 critically ill patients with SARS-CoV-2 infection, 362 (72.4%) received pre-existing comedication. A total of 241/500 patients (48.2%) had a medication history prone to pDDI. Antidiabetics, lipid-lowering drugs, and anticoagulants were among the most frequently used agents with a pDDI. Higher age (OR 1.043; 1.028-1.058; p<0.01) and the number of comorbidities (OR 1.229; 1.119-1.350; p<0.01) were significantly associated with pDDI. 7.4 Conclusion The very patient population that may benefit most from treatment with nirmatrelvir/ritonavir also has the greatest risk of pDDI. Polypharmacy is frequently present in these patients and a conscientious check of the comedication is mandatory before a treatment with nirmatrelvir/ritonavir can be initiated.