Objectives: The aim of this study was to assess the (cost-) effectiveness of screening asymptomatic individuals at intermediate risk of coronary heart disease (CHD) for coronary artery calcium with computed tomography (CT). Background: Coronary artery calcium on CT improves prediction of CHD. Methods: A Markov model was developed on the basis of the Rotterdam Study. Four strategies were evaluated: 1) current practice; 2) current prevention guidelines for cardiovascular disease; 3) CT screening for coronary calcium; and 4) statin therapy for all individuals. Asymptomatic individuals at intermediate risk of CHD were simulated over their remaining lifetime. Quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios were calculated. Results: In men, CT screening was more effective and more costly than the other 3 strategies (CT vs. current practice: +0.13 QALY [95% confidence interval (CI): 0.01 to 0.26], +$4,676 [95% CI: $3,126 to $6,339]; CT vs. statin therapy: +0.04 QALY [95% CI: -0.02 to 0.13], +$1,951 [95% CI: $1,170 to $2,754]; and CT vs. current guidelines: +0.02 QALY [95% CI: -0.04 to 0.09], +$44 [95% CI: -$441 to $486]). The incremental cost-effectiveness ratio of CT calcium screening was $48,800/QALY gained. In women, CT screening was more effective and more costly than current practice (+0.13 QALY [95% CI: 0.02 to 0.28], +$4,663 [95% CI: $3,120 to $6,277]) and statin therapy (+0.03 QALY [95% CI: -0.03 to 0.12], +$2,273 [95% CI: $1,475 to $3,109]). However, implementing current guidelines was more effective compared with CT screening (+0.02 QALY [95% CI: -0.03 to 0.07]), only a little more expensive (+$297 [95% CI: -$8 to $633]), and had a lower cost per additional QALY ($33,072/QALY vs. $35,869/QALY). Sensitivity analysis demonstrated robustness of results in women but considerable uncertainty in men. Conclusions: Screening for coronary artery calcium with CT in individuals at intermediate risk of CHD is probably cost-effective in men but is unlikely to be cost-effective in women.