Many risk factors for coronary artery disease (CAD) have been established by large epidemiological studies. However, some patients without the major risk factors still develop disease. Preliminary analysis of individuals referred for angiography, who had no major risk factors associated with CAD, indicated that apolipoprotein-AI (apoAI) was significantly lower in patients with positive angiograms. The hypothesis that apoAI was an independent risk factor for CAD in low risk populations was put forth. One thousand and seventy-five consecutive patients underwent angiography, lipid analysis, and completed a risk factor questionnaire. Individuals with total cholesterol<5.2 mmol/l, high density lipoprotein (HDL)-cholesterol>0.9 mmol/l, systolic blood pressure<140 mmHg and diastolic blood pressure<90 mmHg, no diabetes, and no family history of premature CAD in first degree relatives were selected. Fifty-four patients met these selection criteria, 29 having positive evidence of CAD and 25 with no evidence of disease. Multivariate analysis revealed that, after adjusting for age and gender, serum apoAI level was the only variable predictive of CAD. This effect was independent of HDL cholesterol level and fractional esterification rate of HDL (FER(HDL)). These results point to an important role for apoAI in the atherogenic process, particularly in populations with no major CAD risk factors. Decreased levels of apoAI or LpAI may initiate atherosclerosis in a highly selected group of low risk patients.