Objective: Patients with coronary heart disease (CHD) suffer from physical limitations, but also from psychological distress. Natriuretic peptides may be involved in the neurobiological processes that modulate psychological adaptation, as they are increased in heart disease and seem to have an anxiolytic-like function. Longitudinal data on this association are scarce.Methods: To assess the relationship between NT-proBNP and anxiety (Hospital Anxiety and Depression Scale (HADS)), we used secondary data from a multicenter trial from baseline to 24 months. Patients (N = 308, 80.8% male, mean age 60.1 years) had stable CHD and moderate levels of depression (HADS >= 8).Results: Multiple linear regression adjusted for age, sex, BMI, and physical functioning revealed NT-proBNP as a significant predictor for anxiety at baseline, 1, 6, 12, 18, and 24 months (all p < .05). Linear mixed model analysis with the six anxiety measures as level-1 variable and NT-proBNP as fixed factor revealed a significant time*NT-proBNP interaction (t(1535.99) = -2.669, p = .01) as well as a significant time*NT-proBNP*sex-interaction (1(1535.99) = 3.277, p = .001), when NT-proBNP was dichotomized into lowest vs. the three highest quartiles.Conclusion: Our results indicate a stable negative association of baseline NT-proBNP with anxiety over two years. In men and women, different pathways modulating this relationship appear to be in effect. Female patients with very low NT-proBNP levels, despite their cardiac disease, show persistently higher levels of anxiety compared to women with higher levels of NT-proBNP and compared to men.