An international multicenter study was undertaken to investigate the epidemiological dynamics of penicillin-resistant pneumococci. We compared the molecular epidemiological characteristics of 205 penicillin-resistant isolates originating from The Netherlands, Thailand, United States, Spain, Greece, Poland, Cuba, Germany, Finland, United Kingdom, South Africa, Hungary, Portugal, Croatia, and the Czech Republic. Eighty-four distinct restriction fragment end labeling (RFEL) types were observed. Twenty-eight genetic types were shared by two or more strains. Five genetic clusters consisted of strains originating from different countries, illustrating dissemination of penicillin-resistant pneumococci among countries. The strains displaying the two predominant RFEL types corresponding with the pandemic clones 23F and 9V were found in 10 and 6 different countries, respectively. This clearly demonstrates the pandemic behavior of these two clones. Twelve out of the 28 genetic clusters contained two or more serotypes. This finding indicates frequent horizontal transfer of capsular genes. Within distinct RFEL types, identical penicillin binding protein (PBP) genotypes were often observed, suggesting a high frequency of horizontal transfer of penicillin resistance genes. The most predominant PBP type was found in 15 distinct RFEL types, comprised 44% of the entire collection, and was observed in 11 countries. The vast majority of the strains belonging to the pandemic clones 23F and 9V shared this predominant PBP type. We hypothesize that the clones 23F and 9V are responsible for the worldwide increase of penicillin-resistance, because they serve as a genetic reservoir for susceptible pneumococci to acquire penicillin resistance.