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Background: In 2024 the risk of hospitalization or death due to COVID-19 is low for most people under age 80 in British Columbia (BC). However, for those at high risk of complications, the antiviral drug combination nirmatrelvir-ritonavir (NMV-r, marketed as Paxlovidᵀᴹ) has shown promise in reducing the composite risk of hospitalization and death from COVID-19. Methods: We evaluated the effectiveness of NMV-r based on data from 3 randomized controlled trials conducted by Pfizer and an observational study conducted by the Therapeutics Initiative in British Columbia. In addition to the impact of NMV-r on COVID-19-related hospitalization or death, we considered the impact of vaccination status on the drug’s effectiveness. Results: The EPIC-HR trial showed a significant reduction in hospitalization and death in high-risk, unvaccinated patients during 2021. In contrast, the 2021-2022 EPIC-SR trial found no benefit for lower-risk, vaccinated patients. The BC observational study found statistically significant risk reductions in high-risk groups, but not in an expanded eligibility group. NMV-r does not affect symptom duration or prevent transmission and is not known to prevent long-COVID. Conclusions: NMV-r may benefit high-risk COVID-19 patients, but it offers little advantage for lower-risk, vaccinated individuals. As Paxlovidᵀᴹ will cost Canadians about $1,400 per treatment, cost-effectiveness is a significant consideration. The ongoing PANORAMIC and CanTreatCOVID clinical trials may provide further insights into NMV-r’s long-term effects on COVID-19 and on healthcare utilization.