The present study was made to shed more light on the clinical importance of early detection of bladder cancer using p53 and p21 mutant proteins as a biomarkers using simple, applicable ELISA techniques. Serum samples were collected from 70 patients , the first group included 50 bladder cancer patients, the second included 20 bilharzial patients ,while the third group consisted of 20 healthy individuals used as control. P53 wild and mutant types showed significant changes (p<0.02 and <0.007,respectively ) in bilharzial patients. Also they showed significant changes in bladder cancer patients with (+ve) lymph node (p<0.02 and p<0.01, respectively) when compared to control as well as it showed great differences between low and high grade ( p< 0.01 and p<0.001) for wild and mutant type. Moreover p53 showed higher sensitivity levels for mutant and wild type in both bilharzial 19.5, 31.2 compared to 23.9 and 35.9%, respectively in bladder cancer one . P21 mutated amino acids were proved to be of significant values in bladder cancer group (p<0.001) compared to bilharzial group. The p21 mutated amino acids showed a correlation with different histological grades for bladder patients, while ARG12 and ASP13 were highly related to bladder cancer with bilharzial history with the notion that ASP13 achieved high sensitivity level to bladder cancer group 91% and 83% for those of bladder cancer with bilharzial history .In conclusion the results of the present study revealed that determination of both p53 and p21 are of great value in the early detection and follow up of bladder cancer patients and screening for risky bilharzial ones.