Abstract Purpose To investigate the clinical impact of three available antivirals for early COVID-19 treatment in a large real-life cohort. Methods Between January and October 2022 all outpatients tested positive for SARS-CoV-2 referring to IRCCS S. Orsola hospital treated with an early antiviral therapy were enrolled. A comparison between patients treated with nirmatrelvir/ritonavir (NTV/r), molnupiravir (MPV) and remdesivir (RDV) was conducted in term of indications and outcome. To account for differences between treatment groups a propensity score analysis was performed. After estimating the weights, we fitted a survey-weighted Cox regression model with inverse-probability weighting with hospital admission/death versus clinical recovery as the primary outcome. Results Overall 1342 patients were enrolled, 775 (57.8%), 360 (26.8%) and 207 (15.4%) in MPV, NTV/r and RDV group, respectively. Median age was 73 (59–82) years, male sex was 53.4%. Primary indication was immunosuppression (438, 32.6%), the median time from symptom onset to drug administration was 3 [2–4] days. Overall, clinical recovery was reached in 96.9% of patients, with hospital admission rate of 2.6%. No significant differences were found in clinical recovery nor hospitalization. Cox regression showed a decreased probability of hospital admission/ death among prior vaccinated patients compared with unvaccinated (HR 0.31 [95%CI 0.14–0.70], p = 0.005]). No difference in hospitalization rates in early treatment compared to late treatment were found. Conclusions No differences among MPV, NTV/r and RDV in terms of clinical recovery or hospitalization were found. Patients not vaccinated had a significant increased risk of hospitalization.