PURPOSE: Understanding the impact of childhood cancer on the family is increasingly important. This study aimed to (1) examine the relationship between child clinical characteristics and health-related quality of life (QOL) among parents of children with cancer or brain tumors, and (2) determine how parental psychosocial factors impact this relationship. METHODS: Using a within-group approach, this study examined 75 children with cancer or brain tumors and their parent. In-person interviewer-assisted surveys assessed sociodemographics, psychosocial factors, and QOL. Child clinical characteristics were obtained through medical record abstraction. Regressions were performed to determine factors related to parental QOL. RESULTS: Children’s activity limitation and active treatment status were associated with worse parental mental QOL (5.4 and 4.4 points lower, respectively; P < 0.05). Adding parental psychosocial characteristics to the model eliminated the relationship between child clinical characteristics and parental mental QOL (P > 0.05 for all child characteristics). CONCLUSIONS: While child clinical characteristics appear to be related to poor parental QOL, this relationship was mediated by caregiver burden and stress. Interventions to reduce burden and stress may mitigate the deleterious effects of caregiving. Systematic screening of parents’ mental and physical health may facilitate interventions and improve the health and well-being of parents and children.