We describe hospitalization trends of invasive pneumococcal disease (IPD) among human immunodeficiency virus-infected individuals <25 years of age since the introduction of highly active antiretroviral therapy (HAART) and the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States, using the Nationwide Inpatient Sample. We estimated national trends of IPD hospitalizations during 3 periods: 1994 to 1995 (pre-HAART and pre-PCV7 era); 1998 to 1999 (HAART and pre-PCV7 era); and 2004 to 2005 (HAART and early PCV7 era). The number of IPD hospitalizations among human immunodeficiency virus-infected children and youth <25 years in the United States declined by 78.7% between 1994/1995 and 2004/2005 (P = 0.03). This decrease was more pronounced among younger children.