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This nationwide cohort study compared the incidence of adverse events of special interest (AESIs) between adenoviral vector-based (ChAdOx1) and mRNA-based (BNT162b2 or mRNA-1273) coronavirus disease 2019 (COVID-19) vaccines. A targeted trial emulation study was conducted using data from the National Health Insurance Service database. Vaccinees aged 18–85 years who had received at least one dose of ChAdOx1 or an mRNA-based vaccine were identified. The 42-day risks of AESIs were calculated. A total of 1 767 539 ChAdOx1 vaccinees were matched exactly with mRNA vaccinees according to their risk factors. The 42-day risks of adverse events were low (∼0 to 176 events per 100 000 persons in both vaccine groups), and the incidence rates of AESIs were comparable between the two platforms, except for a higher occurrence of acute cardiac injury (incidence rate ratio [IRR], 1.22; 95% CI, 1.10–1.35), myocarditis or pericarditis (IRR, 2.14; 95% CI, 1.14–4.04), and arrhythmia (IRR, 1.46; 95% CI, 1.24–1.71) in mRNA vaccinees. The incidence of Guillain–Barré syndrome (IRR, 0.20; 95% CI, 0.06–0.69), vasovagal syncope (IRR, 0.77; 95% CI, 0.62–0.97), radiculopathy (IRR = 0.59, 95% CI, 0.41–0.84), and aseptic arthritis (IRR, 0.81; 95% CI, 0.70–0.93) was significantly lower in mRNA-based vaccinees compared with ChAdOx1 vaccinees. A remarkable platform-dependent difference was observed in the safety profiles of COVID-19 vaccines, particularly for myocarditis or pericarditis and Guillain–Barré syndrome. However, the overall risk of AESIs was low for both vaccine platforms. [ABSTRACT FROM AUTHOR]