Background Fatty acid synthase (FAS) is a valuable lipid enzyme involved in lipid biosynthesis and suggested to contribute in tumor carcinogenesis. Vascular endothelial growth factor (VEGF) is considered a serious angiogenic growth factor in the angiogenic pathway which is a very important in tumor growth and metastasis. Thus, inhibition of lipid biosynthesis and tumor angiogenesis can be new goals for colorectal cancer (CRC) treatment. Aimof the Work The assessment of the expression of FAS and VEGF protein and the relationship between them in CRC with the clinicopathological parameters. Methods The present retrospective study included 63 paraffin blocks previously diagnosed as primary cases of CRC. The slides were subjected to FAS and VEGF immunohistochemical staining using a streptavidin-biotin-peroxidase. The relationships among FAS and VEGF expression and clinicopathological parameters were statistically analyzed. Results The expression rate of FAS was 81% and VEGF was 84.1% in the studied cases. FAS expression was significantly associated with histopathological type (p = 0.02) and grade (p = 0.04), and highly associated with lymph node metastasis and stage (p < 0.001).VEGF was significantly associated with histopathological type (p = 0.01) and tumor depth (p = 0.02); highly associated with grade, lymph node metastasis, and stage (p < 0.001). There was a positive association between FAS and VEGF expression in CRC (p < 0.001). Conclusion FAS and VEGF showed a highly significant expression in the studied primary CRC cases. A significant association was observed between their expressions, suggesting the involvement of FAS in tumor angiogenesis. So they constitute potential targets in cancer prevention and treatment and make FAS an attractive antiangiogenic target.