On November 22, 2022, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr).Nirmatrelvir-ritonavir (Paxlovid), an oral antiviral treatment, is authorized for adults with mild-to-moderate COVID-19 who are at increased risk for progression to severe illness. However, real-world evidence on the benefit of Paxlovid, according to vaccination status, age group, and underlying health conditions, is limited. To examine the benefit of Paxlovid in adults aged ≥18 years in the United States, a large electronic health record (EHR) data set (Cosmos † ) was analyzed to assess the association between receiving a prescription for Paxlovid and hospitalization with a COVID-19 diagnosis in the ensuing 30 days. A Cox proportional hazards model was used to estimate this association, adjusted for demographic characteristics, geographic location, vaccination, previous infection, and number of underlying health conditions. Among 699,848 adults aged ≥18 years eligible for Paxlovid during April-August 2022, 28.4% received a Paxlovid prescription within 5 days of COVID-19 diagnosis. Being prescribed Paxlovid was associated with a lower hospitalization rate among the overall study population (adjusted hazard ratio [aHR] = 0.49), among those who had received ≥3 mRNA COVID-19 vaccines (aHR = 0.50), and across age groups (18-49 years: aHR = 0.59; 50-64 years: aHR = 0.40; and ≥65 years: aHR = 0.53). Paxlovid should be prescribed to eligible adults to reduce the risk of COVID-19associated hospitalization.Paxlovid is an oral antiviral medication that received Emergency Use Authorization by the Food and Drug Administration on December 22, 2021 (1), for use in patients with mild-to-moderate COVID-19 at high risk for progression to severe illness. Eligibility for Paxlovid includes 1) receipt of a positive SARS-CoV-2 test result (including home antigen test), 2) symptoms consistent with mild-to-moderate COVID-19, 3) symptom onset within the past 5 days, 4) age ≥18 years (or age ≥12 years and weight ≥40 kg), 5) one or more risk factors for progression to severe COVID-19, 6) no known or suspected severe renal or hepatic impairment, 7) no history of clinically significant reactions (e.g., toxic epidermal necrolysis or Stevens-Johnson syndrome) to the active ingredients (nirmatrelvir or ritonavir) or other components of the product, and 8) no contraindicated medications. §

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