We used whole-genome sequencing to characterize 199 nonvaccine serotype 35B pneumococcal strains that caused invasive pneumococcal disease (IPD) in the United States during 2015–2016 and related these findings to previous serotype 35B IPD data obtained by Active Bacterial Core surveillance. Penicillin-nonsusceptible 35B IPD increased during post–pneumococcal 7-valent conjugate vaccine years (2001–2009) and increased further after implementation of pneumococcal 13-valent conjugate vaccine in 2010. This increase was caused primarily by the 35B/sequence type (ST) 558 lineage. 35B/ST558 and vaccine serotype 9V/ST156 lineages were implicated as cps35B donor and recipient, respectively, for a single capsular switch event that generated emergent 35B/ST156 progeny in 6 states during 2015–2016. Three additional capsular switch 35B variants were identified, 2 of which also involved 35B/ST558 as cps35B donor. Spread of 35B/ST156 is of concern in view of past global predominance of pathogenic ST156 vaccine serotype strains. Protection against serotype 35B should be considered in next-generation pneumococcal vaccines.