Background: Although different markers are used as diagnostic methods for colorectal carcinoma (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 the role of Transmembrane 9 Superfamily 4 (TM9SF4) and nuclear morphometry in premalignant colonic lesions and colorectal carcinoma. Material and methods: This is a retrospective study carried on 11 ulcerative colitis cases, 16 colonic adenoma cases and 23 colorectal adenocarcinoma cases with 6 normal colon specimens 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 histopathological types of studied cases, lymphovascular invasion, lymph node metastasis, distant metastasis and stage of CRC. There is a significant statistical correlation between nuclear morphometry and different histopathological types of studied cases. Also, there is a significant statistical correlation between area and perimeter nuclear morphometry and perineural invasion and grade of colorectal adenocarcinoma respectively. Conclusion: TM9SF4 may have role in tumorigenesis and development of CRC and also it has a prognostic role in CRC. Nuclear morphometry may have a diagnostic role in CRC.