OBJECTIVE: To examine the combined effects of depressive symptoms and resting heart rate on mortality risk. METHOD: Analysis was performed on data from 5,936 participants in the Whitehall II study with a mean ± SD age of 61 ± 6 years. Depressive symptoms were assessed from 2002 to 2004 using the Center for Epidemiologic Studies Depression Scale (cutoff score for depression at ≥ 16). Resting heart rate was measured at the same study phase via electrocardiogram. Participants were assigned to 1 of 6 risk-factor groups on the basis of depression status (yes/no) and resting heart rate categories (< 60, 60-80, and > 80 beats/minute [bpm]). All-cause mortality was the main outcome in our analysis. Mean follow-up for mortality was 5.6 years. RESULTS: In mutually adjusted Cox regression models, depression (hazard ratio = 1.93, P < .001) and resting heart rate > 80 bpm (hazard ratio = 1.67, P < .001) were independent predictors of mortality. After adjustment for potential confounding and mediating variables, participants with both depression and high resting heart rate had a 3-fold higher (P < .001) risk of death compared to depression-free participants with resting heart rates ranging from 60 to 80 bpm. This risk is particularly marked in participants with prevalent coronary heart disease. CONCLUSIONS: This study provides evidence that the coexistence of depressive symptoms and elevated resting heart rate is associated with substantially increased risk of death compared to those without these 2 factors. This finding suggests the possibility that treatments that improve both depression and resting heart rate might improve survival.