Abstract In light of the ongoing COVID-19 pandemic and the emergence of new SARS-CoV-2 variants, understanding the effectiveness of various booster vaccination regimens is pivotal. In Chile, using a prospective national cohort of 3.75 million individuals aged 20 or older, we evaluate the effectiveness against COVID-19-related intensive care unit (ICU) admissions and death of mRNA-based second vaccine boosters for four different three-dose background regimes: BNT162b2 primary series followed by a homologous booster, and CoronaVac primary series followed by an mRNA booster, a homologous booster, and a ChAdOx-1 booster. We estimate the vaccine effectiveness weekly from February 14 to August 15, 2022, by determining hazard ratios of immunization over non-vaccination, accounting for relevant confounders. The overall adjusted effectiveness of a second mRNA booster shot is 88.2% (95%CI, 86.2–89.9) against ICU admissions and 90.5% (95%CI 89.4–91.4) against death. Vaccine effectiveness shows a mild decrease for all regimens and outcomes, probably linked to the introduction of BA.4 and BA.5 Omicron sub-lineages and the waning of immunity. Based on our findings, individuals might not need additional boosters for at least 6 months after receiving a second mRNA booster shot in this setting.