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Evidence from relatively early in the Covid-19 pandemic suggested that nirmatrelvir–ritonavir (Paxlovid) reduced the risk of hospitalization and mortality. As the SARS-CoV-2 virus has evolved and vaccination rates have increased, it is unclear whether these treatment benefits persist. Now, researchers report results from two open-label, randomized, controlled trials conducted between 2022 and 2024, one in the U.K., the other in Canada. Together, they included about 4000 high-risk outpatients (age, ≥50 years or age, ≥18 with comorbidities) with Covid-19 illness for <5 days who received either nirmatrelvir–ritonavir for 5 days or usual care. Nearly all patients were vaccinated against Covid-19, and about 60% of patients had a comorbidi…