The aim of this study is to explore the Subjective well-being (SWB) of school-going adolescents in Uruguay (N= 325; Mage= 14.67; SD= 1.62). We investigate age- and gender-specific relationships between psychopathology and substance use on the one hand, and subjective well-being on the other hand. Multivariate linear regression analyses, indicated five significant predictors of SWB: three psychopathology factors (depression-anxiety, social anxiety and dissocial behaviour), and age displayed a negative association, while one psychopathology factor (resilience) showed a positive association. When extending the multivariate linear regression analysis with interaction effects, significant interactions appeared regarding gender and resilience and age and substance use. Our study focuses on the necessity to have evidence-based results in order to plan appropriate preventive interventions with adolescents.