Hypoxic preconditioning has been shown to exhibit cardioprotective effects on myocardium from ischemic or reperfusion injury. The specific regulated gene involved in the hypoxia-induced cardioprotective effects is profiled in this study. Young male Wistar rats and ICR mice were exposed to sea level (as normal control) or simulated high altitude for 15 h/day for 2, 4, or 8 weeks, or for 4 weeks at high altitude after 2 weeks at sea level. The left ventricles of the animals were isolated for mRNA isolation and cDNA microarray analysis. Our data demonstrated that hypoxic preconditioning significantly ameliorated cardiac ischemic injury by minimizing the infarct size. After cluster analysis of expression profiles after different courses of hypoxic preconditioning (0, 2, 4, and 8 weeks), 386 genes showed an ascending pattern, whereas 301 genes showed a descending pattern. The ascending genes include several angiogenic factors: FGF receptor 4, vascular endothelial growth factor (vEGF), and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). The microvessel density was also significantly increased in hypoxic hearts. Using Western blotting and immunohistochemical analysis, the protein expression level and localization of CEACAM-1 were observed in hypoxic myocardium. The results also indicated that CEACAM-1 was upregulated as with other hypoxic angiogenic factors, heme oxygenase 1 (HO-1) and hypoxia inducible factor-1alpha (HIF-1α), in in vitro cultured cardiomyocytes (H9c2) after hypoxia treatment and in vivo hypoxic preconditioning. Furthermore, incubation with recombinant vEGF could also increase the expression level of CEACAM-1 in H9c2 cells. These results demonstrated that hypoxic preconditioning resulted in transcriptional changes, and some of these genes have been correlated with angiogenesis. The HIF-1/vEGF/CEACAM-1 pathway might be important for hypoxia-induced angiogenesis in the heart during hypoxic preconditioning.