Trends in serotype incidence and susceptibility (1997 to 2008) of Spanish Streptococcus pneumoniae pleural isolates (n = 831) were explored. Penicillin (oral) nonsusceptibility rates and the incidence of 7-valent pneumococcal conjugate vaccine (PCV-7) serotypes showed decreasing trends (R(2) ≥ 0.600; P ≤ 0.002). The incidence of serotypes 1 and 19A showed increasing trends (R(2) ≥ 0.759; P < 0.001), with no trends for serotype 3. Serotypes 19A, 1, and 3 represented 85% of pediatric isolates in 2008. In serotype 19A, the penicillin nonsusceptibility rate was 82.4% in 2008, associated with amoxicillin and cefotaxime nonsusceptibility in 21.4% of isolates. Inclusion of these serotypes in new vaccines offers the broadest coverage.