OBJECTIVES: A number of studies evaluated different predictors of health-related quality of life (HRQOL) in children and adolescents with epilepsy, but the findings of these studies were often contradictory and it was not possible to draw general conclusions. Therefore, this review was organized with the aims to identify in a systematic way the predictors of HRQOL in pediatric epilepsy.  METHODS: Searches of the literature in Pubmed, Scopus, and Web of Science, with searches of relevant journals were performed. In total, 14 studies met the inclusion criteria (participant aged up to 18 years, HRQOL was assessed with an epilepsy specific and/or generic questionnaire/s, HRQOL predictors were identified using regression models, and the study was published in a peer-review journal). The methodological quality of the studies was assessed using predefined criteria. RESULTS: All identified studies were cross-sectional with the quality scores ranging 7 (low) – 14 (high) points. Strong evidence was found for age at epilepsy onset (younger age), a number of antiepileptic drugs (AEDs), and parental depression as HRQOL predictors in both, children and adolescents. Moderate evidence was found for attention problems, overall intelligence (lower) and family (i. e. structure, parental anxiety, etc.). Specific to adolescents with epilepsy, seizure worry/concerns and side effects of AEDs were found as strong predictors and epilepsy severity, while a number of AEDs as moderate. Weak evidence and inconclusive data exist for other predictors (i.e. social skills, duration of epilepsy, seizure frequency and severity, neuropsychiatric comorbidity, side effects of AEDS, autonomy, social support, victimization, economic status, and so forth). CONCLUSIONS: This systematic review identified age at epilepsy onset, a number of AEDs, and parental depression as strong HRQOL predictors in pediatric epilepsy, but specific to adolescents only, seizure worry/concerns and side effects of AEDs were identified. Other predictors were of lesser importance or were unimportant.