We describe hospitalization trends of invasive pneumococcal disease (IPD) among HIV-infected adolescents and adults since the introduction of highly active antiretroviral therapy (HAART) and the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States, using the nation-wide inpatient sample. We estimated national trends of IPD hospitalizations during 3 periods: 1994-1995 (pre-HAART/pre-PCV7); 1998-1999 (HAART/pre-PCV7); and 2004-2005 (HAART/ early PCV7). The number of IPD hospitalizations among HIV-infected individuals declined 49.2% between 1994/1995 and 2004/2005. Compared with 1994-1995, the adjusted odds ratio for IPD hospitalizations of HIV-infected adolescents and adults in the United States during 2004-2005 was 0.64 (95% confidence interval: 0.54 to 0.77). The decrease was observed after introduction of the PCV7.