- Background The 7-valent pneumococcal conjugated vaccine (PCV7) was introduced to the Israeli national immunization plan (NIP) in July 2009 (administered at age 2, 4 and 12 months), with a fast reduction of invasive pneumococcal disease (IPD) caused by PCV7 serotypes. Starting in November 2010, PCV13 gradually replaced PCV7. Aim To report the impact of PCV7/PCV13 sequential introduction on IPD in Israeli children <5 years. Methods An ongoing nationwide, prospective, population-based, active surveillance. All IPD episodes (Streptococcus pneumoniae isolated from blood and/or cerebrospinal fluid) from July 2004 through June 2013 were included. Results Overall, 2670 IPD episodes were recorded. Incidence of IPD caused by PCV7 + 6A serotypes during the PCV13 period vs. pre-PCV period decreased by 95% (Incidence Rate Ratio [IRR] = 0.05; 95% CI = 0.03–0.09). This reduction was observed in a two-step manner: 90% in the PCV7-period and further 5% in the PCV13-period. The rates of IPD caused by the 5 additional PCV13-serotypes (1, 3, 5, 7F, 19A; 5VT) increased initially by 47%, but subsequently decreased by 79%, resulting in an overall 70% reduction during the entire study period (IRR = 0.30; 0.21–0.44). A two-fold increase in non-PCV13 serotypes IPD was observed (IRR = 2.43; 1.73–3.66). In total, a 63% reduction of all-serotype IPD episodes was observed in children <5 years (69% and 48% in children <2 and 2–4 years old, respectively). Conclusions After initiation of PCV NIP, a rapid and substantial 2-step IPD reduction was observed in children <5 years. The serotype-specific rate reduction reflected the sequential introduction of PCV7/PCV13.