BACKGROUND: The study aimed to screen mutation of human homeostatic iron regulator (HFE) in colorectal carcinoma (CRC) and detect their associations with clinicopathological parameters. METHODS: Expression of HFE was determeined by quantitatie polymerse chain reaction in matched CRC and non-neoplastic colorectal mucosal tissue of 76 patients were recruited. Genomic DNA extracted were subjected to high resolution melt curve analysis and Sanger sequencing to detect mutations of HFE. The associations of the identified mutations with a variety of clinical features were determined. RESULTS: Approximately 60% of CRC showed low HFE expression. Of the ten mutations identified in exons 2 and 4, c.187C>G (H63D), c845G>A (C282Y), c.193A>T (S65C), g.3828T>C, g.5795T>C and g.5728G>A were known mutations. Four novel mutations were discovered; c.184G>A, c.220T>G, c.322A>C and c.324T>C. Heterozygous H63D and C282Y mutations were seen in 71% and 49% of cancer tissue, respectively. Tumour site (p=0.048) and gender (p=0.039) were significantly associated with H63D and C282Y mutation status, respectively. Local spread of cancer was significantly associated with C282Y mutations in CRC cancer and adjacent non-neoplastic tissue (p=0.029 & p=0.004, respectively). There was a statistically significant association between H63D and C282Y negativity in matched non-neoplastic colorectal mucosa tissue and pathological staging of cancer (p=0.047 & p=0.001, respectively). Patients with H63D and C282Y mutations in cancer tissue tends to have higher survival rates. CONCLUSION: HFE mutations are common in CRC and are associated clinicopathological parameters, implying the potential clinical significance of HFE mutations in colorectal carcinogenesis.