The aim of this study was to examine the role of school variables and sense of coherence (SOC) in the explanation of health. For this purpose, data were collected from a representative sample of adolescents, aged 13 to 18 years, selected for the Health Behavior in School-aged Children survey in Spain. Using Structural Equation Modelling, three nested models were tested that represented different hypothesized models of the relationships among school factors, SOC and health. According to goodness-of-fit indices, in the best model, school-related stress and SOC mediated the influence of support from classmates and teachers on health, and SOC had a direct effect on stress. The results supported the idea that a supportive school climate and SOC are relevant to adolescents' health. Furthermore, SOC was the most influential variable; apart from its direct positive effect on health, SOC seemed to condition the degree to which students perceived school demands to be stressful. Specifically, students with a high SOC were less likely to suffer from high levels of school-related stress.