Background: COVID-19 vaccines have been essential for reducing the impact of the pandemic, nevertheless, population-based data under real-life conditions are needed to compare their effectiveness in various contexts. The objective of this study was to estimate the effectiveness of vaccines in preventing hospitalization and death from COVID-19 in Colombia under real-life conditions among people aged 18 years and older, according to sex, age, confirmed history of COVID-19 and vaccination series, including the effects of boosters. Methods: This investigation was an observational, retrospective, population-based study based on the Colombian cohort “Esperanza” (what means hop in Spanish). A total of 14,213,409 individuals aged 18 years and older were analyzed, who were matched in a 1:1 ratio of vaccinated to unvaccinated. The study groups consisted of unvaccinated individuals, those with a complete series (CS) and individuals with a CS plus booster. The vaccinated individuals received either homologous or heterologous vaccinations with Ad26.COV2-S, BNT162b2, ChAdOx1 nCoV-19, CoronaVac and mRNA-1273 vaccines. Follow-up was conducted between February 2021 and June 2022. Cox proportional hazards models were used, adjusted for potential confounders, to estimate the effectiveness of different vaccination series in preventing hospitalization and death. Results: For adults aged 18 years and older, the overall effectiveness of the vaccines in preventing hospitalization was 82.7% (95% CI 82.1 - 83.2) for CS and 80.2% (95%CI 78.7 - 81.6) for CS + booster. The effectiveness in preventing death was 86.0% (95%CI 85.5 - 86.5) for CS and 83.1% (95%CI 81.5 - 84.5) for CS + booster. Effectiveness decreased with age. While all efficacies were high, CoronaVac offered significantly lower protection, although this improved with a booster. Conclusions: Real-world evidence shows that the vaccines studied offer good protection for preventing hospitalization and death from COVID-19 among adults in Colombia. To control the pandemic, reduce the burden of disease and protect national health systems, mass vaccination should continue to be a strategic priority, especially in low- and middle-income countries.