Abstract—Elevated levels of tissue-type plasminogen activator antigen (tPA), fibrinogen, and fibrin D-dimer predict coronary artery disease (CAD) events and stroke. These factors, possibly in association with insulin resistance, may be important in families in which CAD has become clinically apparent at a premature age. From 125 patients with angiographically confirmed, premature CAD, 175 healthy male relatives (age 65 years) were identified. One hundred seventy-five healthy volunteers of similar age and without any family history of CAD were recruited. There were no differences between relatives and controls in terms of conventional CAD risk factors, cigarette smoking, alcohol consumption, or cardiorespiratory fitness. Estimated insulin resistance and plasminogen activator inhibitor 1 levels were not increased in relatives. Fibrin D-dimer, tPA, and fibrinogen levels were elevated in relatives compared with controls, 55 (52 to 58) ng/mL versus 49 (45 to 53) ng/mL, P<0.01, for D-dimer; 8.0 (7.5 to 8.6) ng/mL versus 5.6 (5.2 to 6.1) ng/mL, P<0.001, for tPA; and 3.0 (2.9 to 3.1) g/L versus 2.8 (2.7 to 2.9) g/L, P<0.05, for fibrinogen. These differences remained after adjustment for correlates, including fibrinogen, age for D-dimer, and features of the insulin resistance syndrome for tPA. tPA and D-dimer levels are elevated in the healthy, male, first-degree relatives of patients with premature CAD. This association is independent of potential confounding factors.