The absence of coronary calcification is associated with an excellent prognosis. However, a calcium score of zero does not exclude the presence of coronary artery disease (CAD) or the possibility of future cardiovascular events. Our aim was to study the prevalence and predictors of coronary artery disease in patients with a calcium score of zero. Prospective registry consisted of 3,012 consecutive patients that underwent cardiac CT (dual source CT). Stable patients referred for evaluation of possible CAD that had a calcium score of zero (n = 864) were selected for this analysis. The variables that were statistically significant were included in a multivariable logistic regression model. From 864 patients with a calcium score of zero, 107 (12.4%) had coronary plaques on the contrast CT (10.8%, n = 93 with nonobstructive CAD and 1.6%, n = 14 with obstructive CAD). By logistic regression analysis, the independent predictors of CAD in this population were age >55 years [odds ratio (OR) 1.63 (1.05-2.52)], hypertension [OR 1.64 (1.05-2.56)] and dyslipidemia [OR 1.54 (1.00-2.36)]. In the presence of these 3 variables, the probability of having coronary plaques was 21%. The absence of coronary artery calcification does not exclude the presence of coronary artery disease, but the prevalence of obstructive disease is very low. In this population, the independent predictors of CAD in the setting of a calcium score of zero were hypertension, dyslipidemia, and age above 55 years. In the presence of these 3 predictors, the probability of having CAD was almost 2 times higher than in the general population.