The aim of the study was to evaluate health-related quality of life (HRQoL) in children and adolescents with type 1 diabetes mellitus (T1DM) in Greece compared with healthy controls and to identify the effect of age, gender, age of onset of disease, and metabolic control on perceptions of HRQoL. A total of 117 children and adolescents with T1DM aged 5-18, their parents, and 128 matched healthy children and adolescents participated. Children and adolescents completed PedsQL™ 4.0 Generic Core Scales. Children and adolescents with T1DM also completed the PedsQL™ 3.0 Diabetes Module, while their parents completed the proxy-reports of both the PedsQL™ 4.0 Generic Core Scales and the PedsQL™ 3.0 Diabetes Module. The results demonstrated that children and adolescents with T1DM had lower general HRQoL compared with healthy matched children and adolescents. Parents of children and adolescents with diabetes reported that the illness has a greater affect on their children's lives than the children themselves. Finally, the results indicated that later age of onset of diabetes, less hyperglycemic episodes, lower glycosylated hemoglobin (HbA1c), older age, and male gender were associated with better general HRQoL and diabetes-specific HRQoL. The findings have implications for designing effective therapeutic interventions aimed at improving the HRQoL of children and adolescents with T1DM.