This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Chilean National Immunization Program (NIP) in January 2011 with a 3+1 schedule (2, 4, 6 and 12 months) without catch-up vaccination. We evaluated the effectiveness of PCV10 on pneumonia morbidity and mortality among infants during the first two years after vaccine introduction. Methods: This is a population-based nested case-control study using four merged nationwide casebased electronic health data registries: live birth, vaccination, hospitalization and mortality. Children born in 2010 and 2011 were followed from two moths of age for a period of two years. Using four different case definitions of pneumonia hospitalization and/or mortality (all-cause and pneumonia related deaths), all cases and four randomly selected matched controls per case were selected. Controls were matched to cases on analysis time. Vaccination status was then assessed. Vaccine effectiveness (VE) was estimated using conditional logistic regression. Results: There were a total of 497,996 children in the 2010 and 2011 Chilean live-birth cohorts. PCV10 VE was 11.2% (95%CI 8.5-13.6) when all pneumonia hospitalizations and deaths were used to define cases. VE increased to 20.7 (95%CI 17.3-23.8) when ICD10 codes used to denote viral pneumonia were excluded from the case definition. VE estimates on pneumonia deaths and all-cause deaths were 71.5 (95%CI 9.0-91.8) and 34.8 (95% CI 23.7-44.4), respectively. Conclusion: PCV10 vaccination substantially reduced the number of hospitalizations due to pneumonia and deaths due to pneumonia and to all-causes over this study period. Our findings also reinforce the importance of having quality health information systems for measuring VE.