Summary Objective To describe the epidemiology of invasive pneumococcal disease (IPD) in a predominantly minority population with low childhood immunization rates and high HIV prevalence, during the early childhood pneumococcal vaccine (PCV7) era. Methods A retrospective cases series analysis of 131 patients diagnosed with IPD at University Hospital in Newark, NJ from 2000 through 2005, and who had their pneumococcal isolates serotyped, was conducted. Changes in IPD over time were analyzed with the Cochran-Armitage test and linear regression. Multivariate logistic regression was conducted to determine risk factors for non-vaccine type IPD. Results Ninety-two percent of cases occurred in older children (≥5 years) and adults, with 53.4% occurring in the 34–49 year-old age group. 90% of cases were black and 48% were HIV-infected. Among cases five years or older, there was a significant decrease in the proportion of IPD caused by vaccine serotypes (2000: 45.5%, 2001: 50.0%, 2002: 31.8%, 2003: 30.0%, 2004: 0.0%, 2005: 0.0%; p < 0.0005). Concomitantly, PCV7 immunization rates among Newark infants increased (2002: 30.5%, 2003: 58.1%, 2004: 70.9%, 2005: 75.6%). Risk factors for non-vaccine type IPD included year of diagnosis and older male. Conclusion At-risk populations, with high HIV prevalence and relatively low infant PCV7 immunization rates, may still be benefiting from PCV7-related herd protection effects.