BACKGROUND: The individual risk of severe outcomes following COVID-19 is poorly understood in populations with prior immunity. The lack of contemporary estimates limits support of timely diagnosis and antiviral treatment for individuals most likely to benefit. OBJECTIVE: To determine the risk of severe outcomes following COVID-19 within strata of comorbidities, including patients without documented infection. DESIGN: Population-based cohort study utilizing electronic medical records and g methods to account for selection bias in the documentation of COVID-19 illnesses. SETTING: A large health system in northeastern United States. PATIENTS: Adults with increased risk conditions (90% vaccinated) and COVID-19 from June to December 2022. MEASUREMENTS: Incidence of composite of inpatient admission within 14 days and death within 28 days of COVID-19 diagnosis. RESULTS: An estimated 265,248 patients with at least one increased risk condition developed COVID-19, including 76,996 documented cases. Severe outcomes occurred in 3344 (1.3%) patients following COVID-19- 3147 (1.2%) hospitalizations and 376 (0.14%) deaths. In the absence of treatment, individuals with few increased risk conditions (MASS of 3 or less) accounted for 57% of infections and 0.7% developed severe outcomes. In contrast, 2.3% of patients with multiple increased risk conditions (MASS 4 or greater) or severe immunocompromise experienced severe outcomes, including 81% of deaths. The observed risk reduction with antiviral treatment was -0.1% (-0.2 to 0.02%), -0.6% (-0.9 to -0.4%), -1.3% (-2 to -1%), and -1.9% (-3 to -1%) for patients with MASS 3 or less, MASS 4 and 5, MASS 6 or greater, and severe immunocompromise, respectively. LIMITATIONS: Estimated number COVID-19 cases cannot be directly verified. CONCLUSIONS: Individuals with multiple medical conditions remain at substantial risk for severe outcomes of COVID-19 and benefit from treatment.