The purpose of the present study was to assess the impact of clinical presentation and pretest likelihood on the relation between coronary calcium score (CCS) and computed tomographic coronary angiography (CTA) to determine the role of CCS as a gatekeeper to CTA in patients presenting with chest pain. In 576 patients with suspected coronary artery disease (CAD), CCS and CTA were performed. CCS was categorized as 0, 1 to 400, and >400. On CT angiogram the presence of significant CAD (≥50% luminal narrowing) was determined. Significant CAD was observed in 14 of 242 patients (5.8%) with CCS 0, in 94 of 260 patients (36.2%) with CCS 1 to 400, and in 60 of 74 patients (81.1%) with CCS >400. In patients with CCS 0, prevalence of significant CAD increased from 3.9% to 4.1% and 14.3% in nonanginal, atypical, and typical chest pain, respectively, and from 3.4% to 3.9% and 27.3% with a low, intermediate, and high pretest likelihood, respectively. In patients with CCS 1 to 400, prevalence of significant CAD increased from 27.4% to 34.7% and 51.7% in nonanginal, atypical, and typical chest pain, respectively, and from 15.4% to 35.6% and 50% in low, intermediate, and high pretest likelihood, respectively. In patients with CCS >400, prevalence of significant CAD on CT angiogram remained high (>72%) regardless of clinical presentation and pretest likelihood. In conclusion, the relation between CCS and CTA is influenced by clinical presentation and pretest likelihood. These factors should be taken into account when using CCS as a gatekeeper for CTA.