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Marketing authorization holders of vaccines typically need to report brand-specific vaccine effectiveness (VE) to the regulatory authorities as part of their regulatory obligations. COVIDRIVE (now id. DRIVE) is a European public-private partnership for respiratory pathogen surveillance and studies of brand-specific VE with long-term follow-up. We report the final VE results from a two-dose primary series AZD1222 (ChAdOx1 nCoV-19) vaccine schedule in ≥18-year-old individuals not receiving boosters. Patients (N = 1,333) hospitalized with severe acute respiratory infection at 14 hospitals in Austria, Belgium, Italy, and Spain were included in the test-negative case-control study in 2021-2023. Absolute VE was calculated using generalized additive model (GAM), generalized estimating equation (GEE), and spline-based area under the curve (AUC, measuring VE up to 6 months after the last dose of AZD1222). Overall VE (against coronavirus disease 2019 [COVID-19] hospitalization) of an AZD1222 primary series was estimated as 65% using GEE (95% confidence interval [CI]: 52.9-74.5), and 69% using GAM (95% CI: 50.1-80.9) over the 22-month study period (comparator group: unvaccinated patients). The AUC of the spline-based VE estimate was 74.1% (95% CI: 60.0-88.3). VE against hospitalization in study participants who received their second AZD1222 dose 2 months or less before hospitalization was 86% using GEE (95% CI: 77.8-91.4), 93% using GAM (95% CI: 67.2-98.6). During this study period, where mainly the severe acute respiratory syndrome coronavirus 2 Omicron variant was circulating, a two-dose primary series AZD1222 vaccination conferred protection against COVID-19 hospitalization up to at least 6 months after the last dose., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Public Health Association.)