The current methods for detecting circulating tumor cells (CTCs) suffer from several drawbacks. We report a novel method that is based on a chimeric virus probe and can detect CTCs with extremely high specificity and sensitivity. Moreover, it exclusively detects live CTCs, and its detection efficacy is not impacted by the variation of epithelial cell adhesion molecule (EpCAM) expression. The chimeric virus probe is composed of a capsid from human papillomavirus that provides the detection with high specificity and an SV40-based genome that can amplify extensively inside CTCs and, hence, endows the detection with high sensitivity. Furthermore, different marker genes can be incorporated into the probe to provide detection with versatility. These unique capabilities will likely improve the validity and utility of this CTC detection in several clinical applications, which is one of the drawbacks suffered by many of the current CTC detection methods.