This study examines quality of life (QOL) among school-aged children with perinatally acquired HIV infection and compares QOL outcomes between treatment groups that differ according to the use of protease inhibitor (PI) combination therapy (PI therapy). To gain insights into how PI therapy might influence QOL, associations between severity of illness and QOL were also investigated. Cross-sectional data for 940 children, 5 to 18 years of age, who were enrolled in Pediatric AIDS Clinical Trials Group Late Outcomes Protocol 219 were used to examine domains of caregiver-reported QOL, as assessed with the General Health Assessment for Children, during 1999. The General Health Assessment for Children is an age-specific, modular, QOL assessment that was developed for the study with previously validated measures. QOL differences between treatment groups were estimated with linear and logistic regressions that controlled for sociodemographic characteristics (age, gender, race/ethnicity, maternal/caregiver education, and respondent) and severity-of-illness indicators related to receipt of PI therapy (AIDS status, log(10) CD4+ cell counts, and height-for-age z scores). The mean age of participants was 9.7 years. Most children were non-Hispanic black (54%) or Hispanic (31%), and 49% of the participants were female. At the 1999 study visit, approximately 14% of children had severe immune suppression (<15% CD4+ cells), whereas 62% of children had > or =25% CD4+ cells, ie, no immune suppression. Participants did exhibit some lag in growth, with mean height and weight z scores of -0.70 and -0.20, respectively. Twenty-eight percent of the children were reported to have met criteria for AIDS at study entry (1993-1999). When treatment groups were compared, children receiving PI therapy (72%) were older, had lower CD4+ cell percentages, and had lower height and weight z scores than did those receiving non-PI therapies. They were also more likely to have met criteria for AIDS at study entry. The most commonly used PIs were ritonavir (46%) and nelfinavir (63%). Health perceptions ratings for most children were at the upper end of the scale, whereas ratings for 25% of the children ranged over the lower 70% of scale scores. Almost one half of the children had at least some limitations in physical functioning, with more frequent limitations in energy-demanding activities (46%) than in basic activities of daily living (32%). The Behavior Problems Index was used to assess psychologic functioning. The mean total Behavior Problems Index score (9.34) and the proportion of children with extreme scores (23%) were consistent with values reported for chronically ill children and those at social and economic risk. One or more limitations in social/school functioning were reported for 58% of children. More than one third of the children (38%) experienced > or =1 physical symptoms that were at least moderately distressing. Health perceptions, physical functioning, psychologic functioning, social/school functioning, and overall HIV symptom scores did not differ between treatment groups. However, receipt of PI therapy was associated with an increased rate of diarrhea (28 vs 13%; adjusted odds ratio: 2.59; 95% confidence interval: 1.74-3.85). Severity of illness was associated with QOL in all domains except psychologic functioning. Higher log(10) CD4+ cell counts, higher height-for-age z scores, and absence of AIDS at study entry were independently associated with fewer social/school limitations and better HIV symptom scores. Health perceptions and physical functioning scores were associated with log(10) CD4+ cell counts and height z scores, respectively. QOL among children receiving PI therapy differed little from that among children receiving non-PI therapy, despite clinical indications of more advanced disease. Importantly, the study found no evidence of direct negative effects of PI therapy on QOL outcomes, other than an increased rate of diarrhea. Findings suggest that the effects of PI combination therapies to slow or to prevent disease progression and to increase CD4+ cell counts and height growth have the potential to improve QOL among children with HIV infection. However, many children do experience a constellation of functional impairments indicated by behavioral problems and clinical symptoms, with limitations in activities and in school performance. Comprehensive health services will continue to be required to minimize long-term illness and disability and to maximize children's potential as they move into adolescence and adulthood.