Objective: To evaluate the relationship between cognitive functioning and medication adherence in children and adolescents with perinatally acquired HIV infection. Methods: Children and adolescents, ages 3-18 (N = 1,429), received a cognitive evaluation and adherence assessment. Multiple logistic regression models were used to identify associations between adherence and cognitive status, adjusting for potential confounding factors. Results: Children's average cognitive performance was within the low-average range; 16% of children were cognitively impaired (MDI/FSIQ <70). Cognitive status was not associated with adherence to full medication regimens; however, children with borderline/low average cognitive functioning (IQ 70-84) had increased odds of nonadherence to the protease inhibitor class of antiretroviral therapy. Recent stressful life events and child health characteristics, such as HIV RNA detectability, were significantly associated with nonadherence. Conclusion: Cognitive status plays a limited role in medication adherence. Child and caregiver psychosocial and health characteristics should inform interventions to support adherence. © The Author 2008. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved.