Background: The pneumococcal polysaccharide vaccine (PPV) can prevent invasive pneumococcal disease (IPD) in the elderly and those with certain underlying illnesses. However, vaccine uptake remains suboptimal. Identification of missed opportunities for vaccination could guide new strategies for improving uptake. Missed opportunities for vaccination were defined as one or more visits to a hospital, emergency room (ER), or main provider in the 2 years before infection among unvaccinated, adult IPD case-patients with a vaccine indication. Methods: Adults aged 18 years or older with IPD were identified in six Active Bacterial Core surveillance/Emerging Infections Program Network sites during a 1-year period in 2001 to 2003. Using chart review, patient/proxy interview, a main provider questionnaire, and vaccine questionnaires from additional providers, data were collected on demographics, vaccine indications, vaccine status, and recent healthcare encounters. Results: A total of 1878 cases were enrolled, and 83% had a vaccine indication. Of the 1177 cases with a vaccine indication and sufficient information on recent healthcare encounters, 617 (52%) were unvaccinated. Of these, 566 (92%) had one or more opportunities for vaccination, 54% were hospitalized, 58% had ER visits, and 76% visited their main provider in the 2 years before illness. The number of visits to main providers (median=6) was higher than hospitalizations (median=1), and ER visits (median=1). Conclusions: One or more missed opportunities for vaccination were documented in nearly all unvaccinated IPD case-patients with a vaccine indication. Most visited their main provider multiple times. Implementation of systematic PPV programs in outpatient settings will likely increase pneumococcal vaccine uptake among high-risk adults.