Despite widespread pneumococcal vaccination of children and adults, invasive pneumococcal disease (IPD) remains prominent. Using our database of all Streptococcus pneumoniae infections at the Veterans Affairs Medical Center, Houston, Texas, since 2000, we reviewed cases of IPD, defined as the isolation of pneumococci from any normally sterile body site. In 136 cases, the mean age of patients was 63 years; 43% were African American, a higher proportion than the 30% served by our hospital. One hundred sixteen patients (85%) had pneumonia, of whom 3 also had empyema. Seven had bacteremia with no apparent source, 5 meningitis, 5 spontaneous bacterial peritonitis, 3 septic arthritis, 2 endocarditis, and individual patients had osteomyelitis and/or localized abscesses. One hundred twenty-one patients (89%) had > or =1 underlying condition associated with susceptibility to pneumococcal infection, and another 8 (6%) were aged >65 years old. Thus only 5% of patients lacked a condition for which 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended. Fifty-five percent had been vaccinated; similar proportions of vaccine serotypes infected previously vaccinated and nonvaccinated patients. All but 2 isolates were fully susceptible to penicillin and cefotaxime as currently defined. Consistent with substantial replacement of infecting serotypes since the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), none of the predominant infecting serotypes was included in PCV7, although all except for 6A were contained in PPV23. The overall mortality at 30 days was 16% and was similar in vaccinated and nonvaccinated subjects. IPD causes a wide spectrum of disease. Mortality is substantial. PPV23 is clearly not fully protective.