The pathways between differentiation of self and health remain only partly elucidated. This cross-cultural study sought to test Bowen's hypothesis about the associations between differentiation, stressful life events, and physical and psychological health, in a sample of 466 Spanish adults. Results show that people with higher levels of differentiation were less prone to physical ailments (e.g., heart disease, cancer, or blood disorders) and psychological symptoms (e.g., depression or anxiety). Further, differentiation mediated the association between stress (i.e., perceived negativity of stress in the past year and number of stressful events across the lifetime) and physical and psychological health. The current research provides cross-cultural empirical evidence for the links between differentiation and mind and body health in a Mediterranean culture.