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Background Single-dose vaccination was widely recommended in the pre-Omicron era for persons with previous SARS-CoV-2 infection. The effectiveness of a second vaccine dose in this group in the Omicron era is unknown. Methods We linked nationwide population registries in Spain to identify community-dwelling individuals aged 18–64, with a positive SARS-CoV-2 test before single-dose mRNA vaccination (mRNA-1273 or BNT162b2). Every day between 3 January and 6 February 2022 we matched 1:1 individuals receiving a second mRNA vaccine dose and controls on sex, age, province, first dose type and time, month of primary infection, and number of previous tests. We then estimated Kaplan–Meier risks of confirmed SARS-CoV-2 reinfection. We performed a similar analysis in a Delta-dominant period, between 19 July and 30 November 2021. Results In the Omicron period, estimated effectiveness (95% CI) of a second dose was 62.2% (58.2–66.4%) 7–34 days after administration, similar across groups defined by age, sex, type of first vaccine, and time since the first dose. Estimated effectiveness was 65.4% (61.1–69.9%) for mRNA-1273 and 52.0% (41.8–63.1%) for BNT162b2. Estimated effectiveness was 78.5% (67.4–89.9%), 66.1% (54.9–77.5%), and 60.2% (55.5–64.8%) when primary infection had occurred in the Delta, Alpha, and pre-Alpha periods, respectively. In the Delta period, the estimated effectiveness of a second dose was 8.8% (−55.3% to 81.1%). Conclusions Our results suggest that, over 1 month after administration, a second dose of mRNA vaccine increases protection against SARS-CoV-2 reinfection with the Omicron variant among individuals with single-dose vaccination and previously infected with another variant. [ABSTRACT FROM AUTHOR]