OBJECTIVE: Caregivers of children with asthma can become overwhelmed by the burden of care provision. Guided by the socioecological framework, we examined individual and system-level factors associated with caregiver health-related quality of life (HRQoL) among preschool children (aged two to six years) enrolled in a multilevel home- and school-based asthma educational intervention in Baltimore, Maryland. METHODS: The primary outcome was caregiver HRQoL measured at baseline and six months. Independent variables were baseline individual-level factors (caregiver's health literacy, self-efficacy to manage asthma, and depressive symptoms) and system-level factors (barriers to asthma care measured in five subdomains-pragmatics, health knowledge and beliefs, expectations, skills, and marginalization-and neighborhood social cohesion). Multiple regression models were used to assess the association between baseline individual and system-level factors and caregiver HRQoL at baseline and six-month follow-up adjusting for the child's asthma control, caregiver's age, household income, and study arm assignment/intervention. RESULTS: 398 caregivers completed the baseline survey and 328 (82%) completed the six-month follow-up survey. In the adjusted multiple regression model, lower caregiver's health literacy and higher barriers to asthma care related to pragmatics were significantly associated with lower caregiver HRQoL at baseline ( CONCLUSION: Caregiver health literacy and barriers to asthma care related to pragmatics and skills were found to be important determinants of asthma caregiver HRQoL. Addressing these factors may improve the quality of life among caregivers of preschool children with asthma.