Abstract Background The objective of the study was to assess the effect of changes in mental health status on health-related quality of life (HRQOL) in children and adolescents aged 8 - 18 years. Methods A representative sample of Spanish children and adolescents aged 8-18 years completed the self-administered KIDSCREEN-52 questionnaire at baseline and after 3 years. Mental health status was measured using the Strengths and Difficulties Questionnaire (SDQ). Changes on SDQ scores over time were used to classify respondents in one of 3 categories (improved, stable, worsened). Data was also collected on gender, undesirable life events, and family socio-economic status. Changes in HRQOL were evaluated using effect sizes (ES). A multivariate analysis was performed to identify predictors of poor HRQOL at follow-up. Results Response rate at follow-up was 54% (n = 454). HRQOL deteriorated in all groups on most KIDSCREEN dimensions. Respondents who worsened on the SDQ showed the greatest deterioration, particularly on Psychological well-being (ES = -0.81). Factors most strongly associated with a decrease in HRQOL scores were undesirable life events and worsening SDQ score. Conclusions Changes in mental health status affect children and adolescents' HRQOL. Improvements in mental health status protect against poorer HRQOL while a worsening in mental health status is a risk factor for poorer HRQOL.