A physical chronic condition comes with many challenges and negatively impacts the healthrelated quality of life (HRQOL) of those affected. Self-regulation plays an important role in successfully coping with the demands of a chronic condition. In line with a resource-oriented approach, this study aimed to investigate themoderating effect of self-regulation on the relationship between disease severity andHRQOL. For this, 498 adolescents with cystic fibrosis, juvenile idiopathic arthritis, or type-1 diabetes aged of 12-21 years (M= 15.43, SD= 2.07) were recruited through three patient registers. Subjective disease severity, self-regulation (Brief Self-ControlScale), andHRQOL (DISABKIDSChronicGenericMeasure) were examined at two time points (T-1 and T-2, one year apart). Cross-sectional analysis showed significant effects of subjective disease severity and self-regulation on HRQOL. Prospective analysis, in which HRQOL at T1 was controlled for, revealed that disease severity only predicted emotion-related HRQOL at T-2; selfregulation emerged as a predictor for HRQOL subscales independence, emotion, inclusion, exclusion, and treatment. A significantmoderation effect of self-regulation was found on the relationship between disease severity and HRQOL emotion. Our results highlight the positive impact of self-regulation on quality of life, specifically in the context of chronic conditions and represent a starting point for prevention and intervention approaches.