BACKGROUND: Depression and mortality have been studied separately in patients with coronary heart disease (CHD) and in populations healthy at study inception. This does not allow comparisons across risk-factor groups based on the cross-classification of depression and CHD status. OBJECTIVE: To examine effects of depressive symptoms and CHD and their interactive associations on mortality in middle-aged adults followed over 5.6years. DESIGN AND SETTING: A prospective population-based cohort study of 5936 middle-aged men and women from the British Whitehall II study. We created four risk-factor groups based on the cross-classification of depressive symptoms and CHD status. RESULTS: The age-adjusted and sex-adjusted hazard ratios for death from all causes were 1.67 (p<0.05) for participants with only CHD, 2.10 (p<0.001) for those with only depressive symptoms and 4.99 (p<0.001) for those with both CHD and depressive symptoms when compared to participants without either condition. The two latter risk-factor groups remained at increased risk after adjustments for relevant confounders. The relative excess risk due to the interaction between depressive symptoms and CHD for all-cause mortality was 3.58 (95% CI -0.09 to 7.26), showing some evidence of an additive interaction. A similar pattern was also observed for cardiovascular death. CONCLUSIONS: This study provides evidence that depressive symptoms are associated with an increased risk of all-cause and cardiovascular death and that this risk is particularly marked in depressive participants with co-morbid CHD.