Antibiotic-resistant international clones of Streptococcus pneumoniae are increasingly reported in different parts of the world. We investigated the spread of these clones through an active surveillance performed at the Israeli Streptococcal National Center during 1998 and 1999. Isolates were tested for antibiotic susceptibility, serotyped, and genotyped by random amplified polymorphic DNA analysis and pulsed-field gel electrophoresis. Of 437 isolates, 276 (63.4%) were antibiotic resistant and 156 (35%) were penicillin nonsusceptible (PNS). The PNS isolates were less frequently encountered in southern Israel (27 of 136 [20%]) than in other regions (127 of 301 [42%]). Among 276 antibiotic-resistant isolates, 43 fingerprint patterns were observed. The most common clones were 9V/14-a (19.2%), 5-a (17.8%), and 1-a (10%). The 9V/14-a clone was less common, while the 1-a clone was more frequent in the south than in other regions. The 5-a clone was more common in Jerusalem than in other regions. Among the Jewish and Arab populations the most frequent clones were 9V/14-a (20%) and 1-a (25%), respectively. Three international clones, 9V/14-a-Spain9V-3, 6B-a-Spain6B-2, and 5-a-Colombia 5-19, comprised 40% of all antibiotic-resistant isolates and 56% of all PNS isolates. The sevenvalent conjugate vaccine covers 58% of the most common clones, all highly PNS clones, and 94% of the multidrug-resistant clones in Israel, while the nine-valent vaccine covers all of them. The most common antibiotic-resistant invasive pediatric S. pneumoniae clones-mainly the three international ones-contribute significantly to increases in antibiotic resistance. Their geographic distribution varies within the country and between the different populations.