Vaccines against bacterial pathogens can protect recipients from becoming infected with potentially antibiotic-resistant pathogens. However, by altering the selective balance between antibiotic-sensitive and antibiotic-resistant bacterial strains, vaccines may also suppress-or spread-antibiotic resistance among unvaccinated individuals. Predicting the outcome of vaccination requires knowing what drives selection for drug-resistant bacterial pathogens and what maintains the circulation of both antibiotic-sensitive and antibiotic-resistant strains of bacteria. To address this question, we used mathematical modeling and data from 2007 on penicillin consumption and penicillin nonsusceptibility in Streptococcus pneumoniae (pneumococcus) invasive isolates from 27 European countries. We show that the frequency of penicillin resistance in S. pneumoniae can be explained by between-host diversity in antibiotic use, heritable diversity in pneumococcal carriage duration, or frequency-dependent selection brought about by within-host competition between antibiotic-resistant and antibiotic-sensitive S. pneumoniae strains. We used our calibrated models to predict the impact of non-serotype-specific pneumococcal vaccination upon the prevalence of S. pneumoniae carriage, incidence of disease, and frequency of S. pneumoniae antibiotic resistance. We found that the relative strength and directionality of competition between drug-resistant and drug-sensitive pneumococcal strains was the most important determinant of whether vaccination would promote, inhibit, or have little effect upon the evolution of antibiotic resistance. Last, we show that country-specific differences in pathogen transmission substantially altered the predicted impact of vaccination, highlighting that policies for managing antibiotic resistance with vaccines must be tailored to a specific pathogen and setting.