- Pneumococcal infections in adults vary in severity and incidence is affected by childhood vaccination policy. Here, we try to define the host determinants and the interaction with specific serotypes that result in invasive pneumococcal disease (IPD) before an expected effect of pneumococcal conjugate vaccines. A nationwide active surveillance was initiated on July 2009, at the time of national implementation of PCV7 in Israel. The surveillance included all 27 laboratories and medical centers performing blood cultures in Israel, providing all blood and CSF pneumococcal isolates from persons ≥18y. Capture-recapture method assured that >95% of all cases were reported. IPD outcome and medical history were recorded and isolates were serotyped. Four hundred and sixty IPD cases were reported (annual incidence [/100,000] of 9.25). Incidence increased with age, from 2.6 among 18–34y to 66.8 among ≥85y. The most common diagnosis was pneumonia (72.4%), followed by bacteremia with no apparent focus (20.2%). Case fatality rate increased with age and number of comorbidities (34.5% for ≥75y or those with ≥3 comorbidities vs. 9.2–11.2% among <65y or those with no comorbidities; p = 0.015). Variables independently associated with mortality were: age ≥75, chronic renal failure, malignancy, neurosurgery, alcohol abuse, multi-lobar pneumonia and sepsis with no apparent focus. The predominant serotypes in patients 18–49y were 1, 5, 8, 7F and 9V (constituting 56.3% in this age-group vs. 11.9% in ≥75y; p < 0.01). The predominant serotypes among patients ≥75y were 3, 19A, 23F and 14 (40.3% of this age-group vs. 12.9% of 18-49y; p < 0.01). Overall, PCV7 and PCV13 covered 25.6% and 63.7% of isolates, respectively, and 30.9% and 67.9% of isolates in mortality cases respectively. This nationwide active surveillance provides the baseline incidence, mortality rates and risk group distributions of IPD in adults before expected PCV effect.