Numerous studies have found that depression was a strong independent risk factor for incident coronary heart disease (CHD), with increasing risk in those with higher levels of depressive symptoms. The association between measures of inflammation (C-reactive protein, interleukin-6, and soluble intracellular adhesion molecule-1), depressive symptoms, and CHD incidence was examined in 1,794 subjects of the population-based Canadian Nova Scotia Health Survey. There were 152 incident CHD events (8.5%; 141 nonfatal, 11 fatal) during the 15,514 person-years of observation (incidence rate 9.8 events/1,000 person-years). Depression and inflammation were correlated at baseline and each significantly predicted CHD in separate models. When both risk factors were in the same model, each remained significant. The association between depressed group by the Center for Epidemiological Studies-Depression scale (score > or =10 vs 0 to 9) and CHD incidence (hazard rate 1.60, 95% confidence interval 1.12 to 2.27) was not reduced by the addition of inflammatory markers to the model (hazard rate 1.59, 95% confidence interval 1.12 to 2.26). Findings were similar after adjustment for aspirin, lipid-lowering medication, or antidepressant use, and the association did not vary by gender, smoking status, age, obesity, cardiovascular medication use, or antidepressant use. In conclusion, increased inflammation explained only a very small proportion of the association between depression and incident CHD.