Limited studies compared the effectiveness of nirmatrelvir/ritonavir and molnupiravir against a control group on post-COVID-19 conditions. Our study examined the association of nirmatrelvir/ritonavir and molnupiravir with post-acute mortality and hospitalizations among outpatients using real-world outpatient records of COVID-19 designated clinics in Hong Kong. This is an observational study using a target trial emulation framework, involving nirmatrelvir-ritonavir versus no antiviral treatment (Trial 1) and molnupiravir versus no antiviral treatment (Trial 2). Outcomes included post-acute mortality, all-cause hospitalization, and hospitalization due to 13 selected sequelae. Relative effectiveness was assessed by comparing the cumulative incidence between two groups, reported as relative risk (RR), along with risk differences (RD) during day 0-30, 31-180, and 181-360. After screening, 140477 and 96030 patients were included in Trial 1 and 2, respectively. Compared with no treatment, nirmatrelvir/ritonavir-treated patients exhibited a significantly lower risk of post-acute mortality (31-180 days: RR, 0.71
95% CI, 0.54-0.96
RD, 0.20%
181-360 days: RR, 0.64
95% CI, 0.50-0.82
RD, 0.32%) and all-cause hospitalization (31-180 days: RR, 0.82
95% CI, 0.76-0.88
RD, 1.11%
181-360 days: RR, 0.83
95% CI, 0.78-0.89
RD, 1.18%). Patients receiving molnupiravir had a lower risk of 30-day mortality, but no significant beneficial effect was observed for the post-acute outcomes. In conclusion, this study demonstrated the effectiveness of nirmatrelvir/ritonavir in reducing post-COVID-19 outcomes among outpatients. While we observed the short-term effectiveness of molnupiravir in reducing mortality, no protective effect on long-term post-COVID-19 outcomes was observed.