This study characterizes temporal trends in HIV disease progression among perinatally infected children at a clinic in Baja California, Mexico. A total of 73 children were followed, 52% were categorized under US Centers for Disease Control and Prevention (CDC) classification group C with a mean age of 2.3 years (SD ± 3.16) at HIV diagnosis. For the years 1998 to 2001, 2002 to 2003, 2004 to 2005, and 2006 to 2007, highly active antiretroviral therapy (HAART) use increased to 60%, 75%, 83%, and 94% (P < .001) as did mean CD4 percentage of 23.4%, 23.2%, 26.9%, and 29.0%, respectively (P = .009), while HIV plasma RNA log(10) decreased significantly (4.49, 4.23, 4.00, and 3.79, respectively; P = .019). Overall mortality was 31% (23 of 73), with pneumonia being the most common cause of death (43% of all deaths) followed by tuberculosis (22%). Mortality rates declined from 30.4% to 25%, 8.9%, and 9.3% (p = 0.035) for the years 1998 to 2001, 2002 to 2003, 2004 to 2005, and 2006 to 2007, respectively. Kaplan-Meier survival analysis showed that median survival was 11.2 years; 1-, 2-, and 5-year survival was 87%, 83%, and 67%, respectively. These findings document a high but improving trend in morbidity and mortality of children perinatally infected with HIV in Tijuana, Baja California, Mexico.