Background: Baseline depressive symptoms are associated with subsequent adverse cardiovascular (CV) events in subjects with and without diabetes but the impact of persistent symptoms vs. improvement remains controversial. Objective: Examine long-term changes in depressive symptoms in individuals with and without diabetes and the associated risk for adverse CV events. Design: REGARDS is a prospective cohort study of CV risk factors in 30,000 participants aged 45 years and older. Participants: N = 16,368 (16.5% with diabetes mellitus) who remained in the cohort an average of 11.1 years later and who had complete data. Main Measures: Depressive symptoms were measured using the 4-item Centers for Epidemiologic Study of Depression (CES-D) questionnaire at baseline and again at a mean follow-up of 5.07 (SD = 1.66) years. Adjudicated incident stroke, coronary heart disease (CHD), CV mortality, and a composite outcome were assessed in a subsequent follow-up period of 6.1 (SD = 2.6) years. Methods: The association of changes in depressive symptoms (CES-D scores) across 5 years with incident CV events was assessed using Cox proportional hazards modeling. Key Results: Compared to participants with no depressive symptoms at either time point, participants without diabetes but with persistently elevated depressive symptoms at both baseline and follow-up demonstrated a significantly increased risk of incident stroke (HR (95% CI) = 1.84 (1.03, 3.30)), a pattern which was substantially more prevalent in blacks (HR (95% CI) = 2.64 (1.48, 4.72)) compared to whites (HR (95% CI) = 1.06 (0.50, 2.25)) and in those not taking anti-depressants (HR (95% CI) = 2.01 (1.21, 3.35)) in fully adjusted models. Conclusions: The persistence of depressive symptoms across 5 years of follow-up in participants without diabetes identifies individuals at increased risk for incident stroke. This was particularly evident in black participants and among those not taking anti-depressants.