Increasing the uptake of the 13-valent pneumococcal conjugate vaccine (PCV13) in children is expected to alter the serotypes causing invasive pneumococcal disease (IPD) in adults due to herd protection. We characterized 2172 cases of adult IPD in 2015–2018 in Portugal after the introduction of PCV13 in the national immunization plan of 2015. Among the 58 detected serotypes, serotypes 8 (n = 413; 19%), 3 (n = 334; 15%), 22F (n = 148; 7%), 14 (n = 138; 6%), and 19A (n = 116; 5%) were the most frequent. Among PCV13 serotypes, 7F and 19A IPD decreased, but serotype 3 IPD remained stable. The non-PCV13 serotypes were a heterogeneous group, with serotypes 23A and 23B enriched among CSF cases; serotype 8 associated with younger patients; and serotypes 22F, 6C, and 31 associated with older patients. The continued increase of serotype 8 IPD was one of the drivers for the increased coverage of the 23-valent pneumococcal polysaccharide vaccine (PPV23; 80% in 2015–2018). Antimicrobial resistance was associated with older age and serotypes 6C, 11A, 14, 15A, 19A, and 19F. Three years after the introduction of PCV13 in the NIP with an uptake of >95%, the proportion of PCV13 serotypes causing IPD in adults stabilized in Portugal. The direct vaccination of adults may be important in preventing IPD in this age group.