Background: Although different markers are used as diagnostic methods for CRC such as; carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), low sensitivity and low specificity of these markers revealed the importance of searching for other markers. Transmembrane 9 Superfamily 4 (TM9SF4) is autophagic protein involved in multiple stages of tumorigenesis and development. Nuclear morphometry is a method for digital histological analysis which has been subjected to significant technological advances in the last years. Aim: To evaluate Transmembrane 9 Superfamily 4 (TM9SF4) IHC expression and nuclear morphometry in premalignant colonic lesions and colorectal carcinoma. Material and methods: This is a retrospective study carried on 23 colorectal adenocarcinomas, 16 colonic adenomas, 11 ulcerative colitis and 6 normal colon cases as a control. Clinicopathological characteristics of examined cases were correlated with IHC of TM9SF4 and nuclear morphometry. Results: There is a significant statistical correlation between TM9SF4 scoring and different types of studied cases, lymphovascular invasion, lymph node metastasis, distant metastasis and stage of CRC. There is a significant statistical correlation between CRC and premalignant cases regarding nuclear morphometry. Also, there is a significant statistical correlation between area and perimeter nuclear morphometry and perineural invasion and grade of colorectal adenocarcinoma respectively. Conclusion: The results suggested that TM9SF4 has role in tumorigenesis and CRC development and also has a prognostic role in CRC while, nuclear morphometry has a diagnostic role with nuclear morphometry being better than TM9SF4.