Objective: This proof-of-principle pharmacovigilance study used Electronic Health Record (EHR) data to examine the safety of sotrovimab, paxlovid and molnupiravir in prehospital treatment of Covid-19. Method: With NHS England approval, we conducted an observational cohort study using OpenSAFELY-TPP, a secure software-platform which executes analyses across EHRs for 24 million people in England. High-risk individuals with Covid-19 eligible for prehospital treatment were included. Adverse events (AEs) were categorised into events in the drug's Summary of Product Characteristics (SmPC), drug-reactions and immune-mediated. Cox models compared risk across treatments. A pre-pandemic record analysis was performed for comparative purposes. Results: Between 2021–2023, 37,449 patients received sotrovimab, paxlovid or molnupiravir whilst 109,647 patients made up an eligible-but-untreated population. The 28-day rates of AEs were low: SmPC 0.34 per 1000 patient-years (95% CI 0.32–0.36); drug-reactions 0.01 (95% CI 0.01–0.02) and immune-mediated 0.03 (95% CI 0.03–0.04), and similar or lower than the pre-pandemic period. Compared with the eligible but untreated population, sotrovimab and paxlovid associated with a risk of SmPC AE [adjHR 1.36 (95% CI 1.15–1.62) and 1.28 (95% CI 1.05–1.55), respectively], whilst sotrovimab associated with a risk of drug-reactions [adjHR 2.95 (95% CI 1.56–5.55)] and immune-mediated events [adjHR 3.22 (95% CI 1.86–5.57)]. Conclusion: Sotrovimab, paxlovid and molnupiravir demonstrate acceptable safety profiles. Although the risk of AEs was greatest with sotrovimab, event rates were lower than comparative pre-pandemic period.