A prospective laboratory-based multicenter study that collected all adult invasive pneumococcal disease (IPD) episodes from 6 Spanish hospitals before (2008-2009) and after (2012-2013). The 13-valent pneumococcal conjugate vaccine (PCV13) licensure was conducted in order to analyze the impact of PCV13 introduction for children on adult IPD. A total of 1558 IPD episodes were detected. The incidence of IPD decreased significantly in the second period by-33.9% (95% CI,-40.3% to-26.8%). IPD due to PCV7 serotypes (-52.7%; 95% CI,-64.2% to-37.5%) and to PCV13 additional serotypes (-55.0% 95% CI, -62.0% to-46.7%) significantly decreased whereas IPD due to non-PCV13 serotypes remained stable (1.0% 95% CI,-12.9% to 17.2%). IPD due to all PCV13 additional serotypes significantly declined with the exception of serotype 3 (-11.3%; 95% CI-35.0% to 21.1%). IPD due to two non-PCV13 serotypes varied: serotype 6C that rose (301.6%; 95% CI, 92.7% to 733.3%, p<0.001), related to the expansion of ST386(6C), and serotype 8 that decreased (-34.9%, 95% CI,-57.1 to-1.2, p = 0.049), related to a decline of the ST63(8). The recombinant clone ST6521(11A) (variant of ST156(9V)) increased in frequency. The decrease of serotype 19A IPD was linked to a fall in those antibiotic susceptible clones. In the last period, rates of penicillin-and cefotaxime-resistance remained under 10% and 4%, respectively. Adult IPD decreased after the PCV13 introduction in Spain due to herd protection. The spread of multidrug resistant clones (ST386(6C), ST6521(11A)) related to non-PCV13 serotypes needs further surveillance.