Purpose <p>Patients with COVID-19 and immunocompromising conditions are threatened with higher morbidity, mortality and a greater economic burden than immunocompetent persons due to an inadequate immune response to infection and vaccination. Health and economic COVID-19 outcomes in 2021 and 2022, a period during which vaccines became available gradually, were investigated.</p> Methods <p>This retrospective observational study was based on statutory health insurance (SHI) claims data of approximately 2.7 million insurees each of 2021 and 2022, extrapolated to the overall German SHI population. An immunocompromised group was defined via several risk factors. COVID-19-related outcomes were compared to a group without risk factors (immunocompetent group).</p> Results <p>In both years, COVID-19-associated hospitalizations were significantly elevated in the immunocompromised group (33.11% vs 7.88% in 2021, 19.25% vs 2.21% in 2022), as were ICU admission (9.17% vs 1.75% and 3.94% vs 0.32%), mortality (9.70% vs 1.62% and 3.42% vs 0.30%), and average costs for hospitalizations (17,966 € vs 12,769 € and 16,640 € vs 10,853 €). Hospitalization/intensive care unit (ICU) admission rates and COVID-19 associated mortality decreased from 2021 to 2022 in both groups, but more prominently in the immunocompetent group. Consequently, the gap between both groups increased.</p> Conclusion <p>From 2021 to 2022, the health and economic burden of COVID-19 remained substantially elevated in the immunocompromised group, despite availability of vaccines and authorized treatments.</p>