The presence of calcified coronary artery plaque has shown variable association with clinical coronary heart disease (CHD), particularly after adjustment for other risk factors. From 2002 to 2004, as part of the National Heart, Lung, and Blood Institute's Family Heart Study, coronary artery calcium (CAC) scans by 4-slice multidetector computed tomography were performed in 3,359 subjects, including 389 with clinically diagnosed CHD. Among these was a cohort of 2,254 patients who had been asymptomatic at an initial examination 7 to 9 years previously (1994 to 1996), with 111 who had developed newly diagnosed, nonfatal CHD since the initial examination. In cross-sectional analyses, we examined associations between CAC and CHD in the entire group and in the subgroup seen at the initial examination. In the 2 sets of analyses, odds ratios for CHD ranged from approximately 4 in those with CAC scores of 100 to 199 (p <0.01) to >20 in those with CAC scores ≥1,000 (p <0.0001) compared with those with no measurable CAC. This steep gradient of risk persisted after adjustment for risk factors. A quantitative CHD family history score was significantly associated with CHD even after adjusting for all standard risk factors and including CAC in the model. In conclusion, CAC was strongly associated with CHD even after adjustment for standard risk factors and family history contributed independently to CHD risk.