Abstract Background As of December 30, 2021, Ontario long-term care (LTC) residents who received a third dose of COVID-19 vaccine ≥84 days previously were offered a fourth dose to prevent a surge in COVID-19-related morbidity and mortality due to the Omicron variant. Methods We used a test-negative design and linked databases to estimate the marginal effectiveness (4 versus 3 doses) and vaccine effectiveness (VE; 2, 3, or 4 doses versus no doses) of mRNA vaccines among Ontario LTC residents aged ≥60 years who were tested for SARS-CoV-2 between December 30, 2021 and April 27, 2022. Outcome measures included any Omicron infection, symptomatic infection, and severe outcomes (hospitalization or death). Results We included 13,654 Omicron cases and 205,862 test-negative controls. The marginal effectiveness of a fourth dose (with 95% of fourth dose vaccine recipients receiving mRNA-1273) ≥7 days after vaccination versus a third dose received ≥84 days prior was 19% (95% Confidence Interval [CI], 12-26%) against infection, 31% (95%CI, 20-41%) against symptomatic infection, and 40% (95%CI, 24-52%) against severe outcomes. VE (compared to an unvaccinated group) increased with each additional dose, and for a fourth dose was 49% (95%CI, 43-54%), 69% (95%CI, 61-76%), and 86% (95%CI, 81-90%), against infection, symptomatic infection, and severe outcomes, respectively. Conclusions Our findings suggest that compared to a third dose received ≥84 days ago, a fourth dose improved protection against infection, symptomatic infection, and severe outcomes caused by Omicron among long-term care residents. Compared to unvaccinated individuals, fourth doses provide strong protection against severe outcomes, but the duration of protection remains unknown.