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Introduction: To achieve optimized blood glucose concentrations (assessed by HbA1c) and high health-related quality of life (HRQL), children and adolescents with diabetes mellitus type 1 (T1DM) must follow strict disease management strategies. This study aims to investigate HRQL of children and adolescents with T1DM and its association with HbA1c values over the course of 6 months. Methods: Patients aged 7-17 years (n = 203) with T1DM provided HRQL data on a monthly basis. HRQL was measured using the Kids-CAT, a computer-adaptive test (CAT) comprising five generic HRQL domains. HbA1c concentrations were assessed at baseline, at 3 and 6 months. We explored the trajectory of HRQL at the domain level using linear mixed effects models. Further, we investigated the association between HRQL and HbA1c concentrations over time using path analysis models. Results: Children and adolescents with T1DM reported high scores across all HRQL domains over time. However, those with an HbA1c concentrations of >9.0% reported significantly lower scores in physical well-being and parent relations compared with those with an HbA1c concentration of 9.0% reported lower scores in selected HRQL domains. Thus, special attention should be drawn to HRQL of children and adolescents with higher HbA1c concentrations. The minimal relationship between HbA1c and HRQL indicates that the two therapy goals, i.e., achievement and maintenance of glycemic targets and high HRQL, should be considered and evaluated independently in clinical routine. Trial Registration: DRKS00006326 (German Clinical Trial Register), date of registration: August 1st, 2014.