- Background: Since the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States, the need for additional serotype coverage has become clear. Our objective was to assess the potential serotype coverage of PCV7 and of the 2 experimental conjugate vaccines, 10-valent (PCV10) and 13-valent (PCV13), against invasive pneumococcal disease (IPD), acute otitis media (AOM), acute conjunctivitis (AC), and pneumococcal carriage in southern Israel, where PCV7 had not yet been introduced at the time of the study. Methods: Data on isolates were obtained prospectively from children <36 months during 2000–2004. The potential coverage of the PCVs was calculated and analyzed separately for antibiotic-resistant strains. Results: A total of 5497 isolates were collected: 189 from blood or cerebrospinal fluid, 3197 from middle ear fluid, 348 from the conjunctiva, and 1763 from the nasopharynx of healthy children. The serotype coverage of PCV7 for IPD, AOM, AC, and carriage was 44%, 54%, 37%, and 46%, respectively. Serotypes included in PCV7 caused 47 IPD cases per 100,000 children <3 years (54 per 100,000 if serotype 6A is included). PCV10 extended mainly the coverage of IPD, while addition of serotypes 6A and 19A to PCV13 increased the coverage substantially in all entities (84%, 79%, 54%, and 67% in IPD, AOM, AC, and carriage, respectively). PCV13 could prevent >90% of penicillin-, macrolide-, and multidrug-resistant strains associated with IPD and AOM. Conclusions: PCV7 can substantially decrease pneumococcal disease and carriage in Israel, but PCV10 and PCV13 have a significant added benefit. Moreover, PCV13 has an important potential added benefit over PCV7 and PCV10 in reducing disease by drug-resistant Streptococcus pneumoniae.