Objective: Evaluate whether smoking exposure and depressive symptoms accumulated over 25 years are synergistically associated with subclinical heart disease, measured by coronary artery calcification (CAC). Method: Participants (baseline: 54.5% women; 51.5% Black; age range = 18–30 years) were followed prospectively from 1985 to 2010 in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Smoking status was queried yearly from Year 0 to Year 25 to compute packyears of smoking exposure. Depressive symptoms were measured on the Center for Epidemiologic Studies Depression (CES-D) scale every 5 years to compute cumulative scores from Year 5 to Year 25. A three-level multinomial logistic regression was used to evaluate the association between cumulative smoking, cumulative depressive symptoms, and their interaction with moderate-risk CAC (score 1–99) and higher-risk CAC (score ≥100) compared with no CAC (score = 0) at Year 25. Models were adjusted for sociodemographic, clinical, and behavioral covariates. Results: Among 3,189 adults, the cumulative Smoking × Depressive Symptoms interaction was not significant for moderate-risk CAC (p = .057), but was significant for higher-risk CAC (p = .001). For adults with a 30-packyear smoking history, average CES-D scores 2, 10, and 16 were, respectively, associated with odds ratios (95% confidence intervals) 3.40 (2.36–4.90), 4.82 (3.03–7.66), and 6.25 (3.31–11.83) for higher-risk CAC (all ps < .05). Conclusion: Cumulative smoking exposure and cumulative depressive symptoms have a synergistic association with subclinical heart disease, where higher lifetime smoking exposure and depressive symptoms are associated with greater odds of CAC.