Background: Adolescence includes a period (10 to 19 years) of profound biopsychosocial changes, constituting potentially difficult challenges, which may become more pronounced in the presence of a chronic condition and its limitations. Responses are not homogeneous and can be quite variable, depending on various specific individual factors. Research comparing adolescents with or without chronic illness, or comparing across different conditions, has been contradictory, not confirming a direct relationship between the degree of suffering and the chronic condition. Objective: To characterize and assess the impact of 1) having a chronic condition (CC) and 2) how CC affects school participation; and its association with life satisfaction and perception of wellness, controlling for demographic factors: age, gender and family socioeconomic status (SES). Methods: 5050 Portuguese adolescents with an average age of 14 years participated in the Health Behaviour in School-aged Children/WHO (HBSC). Results: The majority of the adolescents with CC reported that their conditions did not affect school participation. Adolescents with CC who indicated that CC affected school participation felt more frequently unwell and presented lower life satisfaction. Being a boy, younger and having high family socio economic status (SES) were identified as predictors of higher life satisfaction; on the other hand, being a girl, older, having lower SES, living with CC and feeling that CC affects school participation are predictors for feeling more frequently unwell. Conclusions: These adolescents showed an increased vulnerability, presenting internalized symptoms and lower life satisfaction. Furthermore, when there was simultaneous occurrence of living with CC and that CC affected school participation, the impact was even higher. Thus, it is crucial that future interventions should include the identified predictors, combined with “listen to the voice” of adolescents, throughout the adaptation process.