Background: Nirmatrelvir/ritonavir is authorized for the treatment of COVID-19 but has several contraindications and potential drug-drug interactions (pDDIs) due to ritonavir-induced irreversible inhibition of cytochrome P450 3A4. We aimed to assess the prevalence of individuals with one or more risk factors for severe COVID-19 along with contraindications and pDDIs due to ritonavir-containing COVID-19 therapy. Methods: Retrospective observational study of individuals with one or more risk factors according to Robert Koch Institute criteria for severe COVID-19 according to German statutory health insurance (SHI) claims data from the pre-pandemic years 2018-2019 based on the German Analysis Database for Evaluation and Health Services Research. Prevalence was extrapolated to the entire SHI population using age-adjusted and sex-adjusted multiplication factors. Results: Nearly 2.5 million fully insured adults, representing 61 million people in the German SHI population, were included in the analysis. In 2019, prevalence of individuals that would have been at risk of severe COVID-19 was 56.4%. Amongst them, the prevalence of contraindications for treatment with ritonavir-containing COVID-19 therapy was approximately 2% according to presence of somatic comorbidities (severe liver or kidney disease). Prevalence of intake of medicines contraindicated for their potential interactions with ritonavir-containing COVID-19 therapy was 16.5% according to Summary of Product Characteristics and 31.8% according to previously published data. The prevalence of individuals at risk of pDDIs during ritonavir-containing COVID-19 therapy without adjustment of their concomitant therapy was 56.0% and 44.3%, respectively. Prevalence data for 2018 were similar. Conclusion: Administering ritonavir-containing COVID-19 therapy can be challenging as thorough medical record review and close monitoring are required. In some cases, ritonavir-containing treatment may not be appropriate due to contraindications, risk of pDDIs, or both. For those individuals, an alternative ritonavir-free treatment should be considered.