Background: Mutations of p 53 may be a possible molecular event related to carcinogenesis in the setting of colorectal cancer (CRC).Aim: Identifying p53 mutational hotspots in pre-cancerous and cancerous colonic lesion obtained from Egyptian patients.Patients and Methods: Hundred biopsy- proven patients with CRC(n=48) , ulcerative colitis(n=24) and adenomatous polyps(28); who were primarily diagnosed by gross endoscopic picture; were recruited from the Gastro-intestinal and Endoscopy Unit, Faculty of Medicine, Cairo University. Tissue biopsy and peripheral blood samples were obtained from all patients. Mutation in p53 gene was evaluated in the DNA achieved from tissue and blood samples using PCR-SSCP silver staining technique followed by automated sequencing for the abnormal bands. Results: P53 mutation was detected in 16.7% and 41.7% of CRC and UC patients respectively while none of the patients with polyps expressed this mutation. Most of the p53 mutation were missense; their type and locations were different from previously detected in western populations. Conclusions: Mutation of p53 protein plays an important role in the early event in UC CRC pathway. The presence of unique characteristic mutational sites in Egyptian patients could represent an important molecular marker for early detection of CRC.