Background: As of September 2022, nearly 1.3 billion doses of COVID-19 vaccine products have been administered in Latin America and the Caribbean, where 27% of global COVID-19 deaths have occurred. This study aimed to estimate the effectiveness of COVID-19 vaccines against lab-confirmed COVID-19 related hospitalizations and deaths among adults in Argentina, Brazil, Chile, and Colombia. Methods: Using a test-negative case control design, we evaluated the effectiveness of a primary vaccination series considering six COVID-19 vaccine products (Sputnik V, mRNA-1273, CoronaVac, ChAdOx1, BNT162b2, Ad26.COV2.S) against lab-confirmed COVID-19 hospitalizations and deaths among 83,708 hospitalized adults from February–December, 2021. Data from hospitalization records, COVID surveillance, and vaccination registries were used. Vaccine effectiveness was estimated using logistic regression ((1-OR) x 100). Findings: The average age of participants was 56.7 (SD = 17.5), and 45,894 (54.8%) were male. Adjusted VE (aVE) estimates for full vaccination against hospitalization were 82% for mRNA-1273 (95% confidence interval (CI) = −30 to 98%), 76% (71%–81%) for BNT162b2, 65% (61–68%) for ChAdOx1, 57% (10–79%) for Sputnik V, 53% (50–56%) for CoronaVac, and 46% (23–62%) for Ad26.COV2.S. Estimates, particularly for CoronaVac, varied by variant. Decreasing aVE was estimated as age increased, particularly for CoronaVac and ChAdOx1. aVE estimates against death were generally higher, with 100% (CI not estimated) for mRNA-1273, 82% (69–90%) for BNT162b2, 73% (69–77%) for ChAdOx1, 65% (60–67%) for CoronaVac, 38% (−75 to 78%) for Sputnik V, 6% (−58 to 44%) for Ad26.COV2.S. Interpretation: Primary series vaccination with available COVID-19 vaccine products was effective against COVID-19 hospitalization and mortality. Effectiveness varied by product and declined with increasing age. Funding: This study was funded by the Pan-American Health Organization (PAHO, World Health Organization (WHO)). PAHO convened and led the study implementation.