Objectives To explore, identify and understand the contribution that biomedical and psychosocial factors make to the assessment of health-related quality of life (HRQL) of children and youth with epilepsy using the CHEQOL-25. Methods We identified and measured variables that may influence HRQL; grouped the variables into four conceptual categories; and used simple and hierarchical linear regressions to model CHEQOL-25 as a function of these variable groupings. Participants were 8-15year olds with epilepsy and their parents. Results 131 child and parent pairs participated. Overall, the unique variances associated with the biomedical and psychosocial variables are R2 =0.22 and 0.29, respectively, for child self-reported HRQL and R2 =0.11 and 0.13, respectively, for parent-proxy report. Conclusions This study increases our understanding of factors that contribute to the expression of HRQL in this population. These results should be interpreted with caution due to the limited sample size and large number of variables.