Context: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome. Although dysregulation of the autonomic nervous system is found to associate with the metabolic syndrome and its dysregulations, no longitudinal study has been performed to date to examine the predictive value of this stress system in the development of the metabolic syndrome. Objective: We examined whether autonomic nervous system functioning predicts 2-year development of metabolic abnormalities that constitute the metabolic syndrome. Design: Data of the baseline and 2-year follow-up assessment of a prospective cohort: the Netherlands Study of Depression and Anxiety was used. Setting: Participants were recruited in the general community, primary care, and specialized mental health care organizations. Participants: A group of 1933 participants aged 18-65 years. Main outcome measures: The autonomic nervous system measures included heart rate (HR), respiratory sinus arrhythmia (RSA; high RSA reflecting high parasympathetic activity), pre-ejection period (PEP; high PEP reflecting low sympathetic activity), cardiac autonomic balance (CAB), and cardiac autonomic regulation (CAR). Metabolic syndrome was based on the updated Adult Treatment Panel III criteria and included high waist circumference, serum triglycerides, blood pressure, serum glucose, and low high-density lipoprotein (HDL) cholesterol. Results: Baseline short PEP, low CAB, high HR, and CAR were predictors of an increase in the number of components of the metabolic syndrome during follow-up. High HR and low CAB were predictors of a 2-year decrease in HDL cholesterol, and 2-year increase in diastolic and systolic blood pressure. Short PEP and high CAR also predicted a 2-year increase in systolic blood pressure, and short PEP additionally predicted 2-year increase in diastolic blood pressure. Finally, a low baseline RSA was predictive for subsequent decreases in HDL cholesterol. Conclusion: Increased sympathetic activity predicts an increase in metabolic abnormalities over time. These findings suggest that a dysregulation of the autonomic nervous system is an important predictor of cardiovascular diseases and diabetes through dysregulating lipid metabolism and blood pressure over time. Copyright © 2013 by The Endocrine Society.