© 2015 Elsevier Ireland Ltd. Background: Recent studies suggest atrial fibrillation (AF) is an independent risk factor for coronary heart disease (CHD). Aims: To determine if alterations in hemostasis or inflammation explain the association between AF and CHD. Methods: C-reactive protein (CRP), D-dimer, factor VIII, and fibrinogen were measured in incident CHD cases (n = 647) and a stratified cohort random sample (CRS, n = 1104) between 2003 and 2007 from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Using a case-cohort approach, Cox models examined whether inflammation or hemostasis biomarkers explained the association between AF and CHD. Results: In participants free of CHD at baseline, 12.2% of CHD cases and 7.1% of the CRS had AF. Over a median follow-up of 4.4 years, all biomarkers were associated with an increased risk of CHD in those with and those without AF after adjusting for CHD risk factors. The association of D-dimer with CHD was greater in those with AF (HR 2.52, 95% CI = 1.49, 4.26) than those without AF (HR 1.34, 95% CI = 1.12, 1.61) (p-interaction = 0.02). Similar interactions were not observed for the other biomarkers. Conclusions: Our results suggest that alterations in D-dimer, a marker of hemostasis, explain the association between AF and CHD. Potentially, D-dimer is a useful biomarker to assess CHD risk in persons with AF.