Background: CMV Virus is one of the most common opportunistic infections in ulcerative colitis patients that leads to more immunological and inflammatory irritation and thus leads to treatment resistance and dysplastic progression. This work aims to evaluate the role of P53 & AMACR as early predictor markers of dysplastic transformation and clinical deterioration in CMV-infected ulcerative colitis patients. Method: Forty CMV-ulcerative colitis and twenty Non-CMV-ulcerative colitis patients with active colitis underwent baseline assessment for clinical endoscopic evaluation, histological evaluation of the degree of inflammation, and dysplasia, and P53/AMACR expression detection. Cases were then classified into four groups, namely, CMV-UC with P53/AMACR, CMV-UC without P53/AMACR, Non-CMV-UC with P53/AMACR, and Non-CMV-UC without P53/AMACR. After 36.16±3.78 months of follow-up, the same assessment was carried out to record the progression parameters of all groups. Results: CMV-UC with P53&AMACR group showed a significant association with clinical, and histological progression 8/22 (36.4%) in compared with CMV-UC without P53/AMACR and the clinical and histological progression was 1/18 (5.6%) and 2/18 (11.1%) respectively and in Non-CMV-UC with P53/AMACR group were 1/9 (11.1%) and 2/9 (22.2%) respectively with (P-value<0.001**) Conclusions: P53/AMACR co-expression is an early indicator of dysplastic progression, treatment resistance, and clinical deterioration. Patients with UC should have a regular examination for CMV infection and early CMV treatment before mutations of p53 and AMACR are overexpressed, as their presence reduces the chances of recovery and accelerates dysplastic progression.