Background In March 2010, 13-valent pneumococcal conjugate vaccine (PCV13) replaced the seven-valent vaccine in the USA. We assessed the effect of PCV13 use on pneumococcus-related admissions to hospital 2 years after the vaccine was introduced, when coverage in children younger than age 5 years had reached 54%. Methods We used data from a private inpatient discharge record database. We extracted age-specific data for admissions to hospital per month (July 1–June 30) for all-cause pneumonia, invasive pneumococcal disease, non-invasive pneumococcal pneumonia, and empyema (all coded by International Classification of Diseases 9) for 2005–12. We also extracted data for urinary tract infection and hospital admission for any reason as control outcomes. We assessed incidences of hospital admission before and after the introduction of PCV13 and used a negative binomial multiple regression model to estimate how much of the change in hospital admissions could be attributed to the vaccine. Findings Our model results showed that PCV13 was associated with significant reductions in hospital admissions for all-cause pneumonia for some children (21% [95% CI 14–28] in children aged <2 years, 17% [7–27] in those aged 2–4 years) and for empyema (50% [95% CI 22–68] for children age <2 years, 46% [21–64] for 2–4 years, and 37% [13–54] for 5–17 years). All-cause pneumonia was significantly reduced in adults aged 18–39 years (12% (6–17) but not for other adult age groups. The vaccine also reduced admissions for invasive pneumococcal pneumonia and non-invasive pneumococcal or lobar pneumonia in children and adults, indicating herd protection, although the reduction was only significant in some age groups. Interpretation Only 2 years into the US programme, PCV13 significantly reduced residual invasive and non-invasive pneumococcal hospital admissions in children younger than 5 years, as well as in some adult age groups. Our study design captured the total prevented hospital burden (directly and indirectly by herd protection) and also showed a reversal of the PCV7 era increase in paediatric empyema related to strain replacement. Funding Pfizer.