Objectives. It is known that the development of colorectal cancer is characterized by a series of events during which the normal epithelium of the colon gradually transforms into cancer, following the sequence from adenoma to carcinoma. Apoptosis plays an important role in the development and maintenance of tissue homeostasis. Hypoxia exists in solid tumors and causes hyperpermeability of the inner mitochondrial membrane leading to the release of cytochrome c and cleavage of caspase 9, thereby activating apoptosis. Currently, there is no agreement in the literature on the prognosis of apoptosis and hypoxia in colorectal cancer. The number of studies examining the expression of caspases and HIF-1a in colorectal cancer is very limited and they did not examine the correlation between expression and patient survival. Patients and Methods. This study included histological samples from 179 patients diagnosed with colon cancer. We used the TUNEL method and caspase-3 labeling to identify the degree of apoptosis while examining the association between the expression of HIF-1α and caspase-9 and tumor pathology and to determine their prognostic significance for colorectal cancer. Results. The results show that lower apoptotic index (AI) measured by the TUNEL method and lower immunohistochemical expression of caspase-3 are associated with shorter disease-free survival and overall survival. HIF-1α and caspase-9 expression correlated with tumor stage, tumor grade, and vascular invasion, and was associated with poor overall and disease-free survival. Increased expression of HIF-1α and caspase-9 is associated with tumor growth, aggressiveness and poor survival in patients with colorectal cancer. Conclusion. Only the apoptotic index (AI) determined by the TUNEL method proved to be an independent indicator of survival. The research results are consistent with the proposed models of colorectal cancer carcinogenesis that emphasize resistance to apoptosis as a determining factor in disease progression and resistance to treatment.