A description of invasive Streptococcus pneumoniae isolates over a 5-year period from blood culture and cerebrospinal fluid culture follows, in Pretoria South Africa January 2005 through December 2009. Isolates were identified using standard microbiological techniques, serotyped, and a MIC determined for penicillin and cefotaxime. A total of 177 isolates were included in the analysis. Eighty percent of patients in the 18- to 45-year age group tested positive for HIV. In children <5 years of age, 66% (n = 49) of serotypes were those present in the heptavalent pneumococcal conjugate vaccine (PCV-7). Fifty-nine percent (n = 29) were from PCV-7 serotypes in the <1-year-old age group. An additional peak of invasive disease was also seen in the 18- to 45-year age group. Only 1 of 177 isolates had resistance to penicillin (MIC ≥2 μg/mL); none was resistant to cefotaxime. The introduction of the PCV-7 vaccine in South Africa will decrease invasive pneumococcal disease caused by vaccine serotypes.