BACKGROUND: Fructose is a very common sugar found in natural foods, while current studies demonstrate that high fructose intake is significantly associated with increased risk of multiple cancers and more aggressive tumor behavior, but the relevant mechanisms are not fully understood. METHODS: Tumor-grafting experiments and in vitro angiogenesis assays were conducted to detect the effect of fructose and the conditioned medium of fructose-cultured tumor cells on biological function of vascular endothelial cells (VECs) and angiogenesis. 448 colorectal cancer specimens were utilized to analyze the relationship between Glut5 expression levels in VECs and tumor cells and microvascular density (MVD). RESULTS: We found that fructose can be metabolized by VECs and activate the Akt and Src signaling pathways, thereby enhancing the proliferation, migration, and tube-forming abilities of VECs and thereby promoting angiogenesis. Moreover, fructose can also improve the expression of vascular endothelial growth factor (VEGF) by upregulating the production of reactive oxygen species (ROS) in colorectal cancer cells, thus indirectly enhancing the biological function of VECs. Furthermore, this pro-angiogenic effect of fructose metabolism has also been well validated in clinical colorectal cancer tissues and mouse models. Fructose contributes to angiogenesis in mouse subcutaneous tumor grafts, and MVD is positively correlated with Glut5 expression levels of both endothelial cells and tumor cells of human colorectal cancer specimens. CONCLUSIONS: These findings establish the direct role and mechanism by which fructose promotes tumor progression through increased angiogenesis, and provide reliable evidence for a better understanding of tumor metabolic reprogramming.