We recently reported a cross-sectional negative relationship between cardiovascular reactivity and depressive symptoms. The present analyses examined the prospective association between reactivity and symptoms of depression 5 years later. At the earlier time point, depressive symptoms, measured using the Hospital Anxiety and Depression Scale (HADS), and cardiovascular reactions to a standard mental stress were measured in 1,608 adults comprising three distinct age cohorts: 24-, 44-, and 63-year-olds. Depression was reassessed using the HADS 5 years later. Heart rate reactions to acute psychological stress were negatively associated with subsequent depressive symptoms; the lower the reactivity the higher the depression scores. This association withstood adjustment for symptom scores at the earlier time point and for sociodemographic factors and medication status. The mechanisms underlying this prospective relationship remain to be determined.