Muscle invasive bladder cancer is an aggressive tumor. Radical cystectomy is considered the standard treatment. However, many patients experience local and distant relapse. The biological behavior cannot be adequately predicted by histological criteria alone. This work aims to evaluate the role of 6 cell cycle and apoptosis regulatory markers (cyclinD1, CDK4, bcl2, bax, p16, and p14) as predictive and prognostic makers in muscle invasive bladder cancer and their relation to the treatment received Patients and methods: One hundred and twenty nine patients with muscle invasive bladder cancer were included, 68 patients underwent surgery alone and 61 patients underwent surgery and postoperative radiotherapy. Immuno-histochemistry and differential PCR were used to determine the expression level of CDK4, bcl2, and bax. P16 and p14 were evaluated for homozygous deletion and/or promoter methylation. For a median follow up of 20 months there was no significant difference between the 2 studied groups (surgery versus surgery and radiotherapy) in terms of disease free or overall survival. Tumor extension, positive lymph nodes, and aberrant expression of cyclin D1, CDK4, bcl2, Bax, p16, p14 were all independent prognostic factors for disease free survival with a p value of 0.006, 0.002, 0.001,< 0.0001, <0.0001, <0.0001, 0.0001, respectively . On the other hand, positive lymph nodes, and aberrant expression of bcl2, bax, p16, and p14 were independent prognostic factors for overall survival with a p value of 0.02 <0.001, <0.001, <0.001, and 0.001 respectively. In the surgery group, cyclin D1, CDK4, p16, and p14 were predictors of loco-regional failure, while bcl2, bax and p14 were predictors of distant metastases. In the surgery and radiotherapy group bcl2, p16 and p14 were predictors of loco-regional failure, while bcl2, bax and p14 were predictors of distant metastases. Cell cycle regulators are good prognostic and predictive markers in muscle invasive bladder cancer. Postoperative radiotherapy for muscle invasive bladder cancer cannot yet be considered in the routine practice and larger studies are still needed to properly evaluate its role taking the molecular profile of the disease in consideration as a risk factor for response to treatment.