The aim of the present study was to determine the role of whole sonicated E.coli O157:H7 antigen and culture filtratedE.coli O157:H7 antigen in protection of mice against this pathogen. To achieve this aim, sixty white mice both sexes with average age ranged 8 ? 10 weeks were equally and randomly divided into four groups as following: 1st group immunized with 0.3 ml of WSECAg protein concentration (3.86 mg/ml) s/c two doses two weeks intervals. 2nd group immunized with 0.3 ml of CFECAg protein concentration (3.33 mg/ml) s/c two doses two weeks intervals. 3rd group served as control positive group. At 27 ? 30 days post immunization skin test and ELISA were done, the 1st , 2nd and 3rd groups were inoculated IP with 0.4 ml bacterial suspension containing 0.45x1010cfu/ml of E.coli O157:H7 isolated from cattle fecal sample. 4th group served as control negative which inoculated with 0.3 ml of normal saline. All animals were sacrificed at ten days of age 15 ? 16 weeks. The results were showed both types of antigens which stimulated both the cellular and humoral immune response that their intensity differ according to the type of antigens, heavy to more heavy bacterial isolation with severe pathological changes were recorded in examined organs (heart, liver, spleen, lung, kidney and brain) of the control positive group while mild to moderate bacterial isolation with mild pathological changes were recorded in examined organs of mice of the immunized group with WSECAg while no growth of bacterial isolation with very mild pathological lesions were reported in examined organs of mice of immunized group with CFECAg post challenge. The results of this study were concluded that both types of antigens produced a good protection against E. coli O157:H7 infection in mice as well as showed that CFECAg was good stimulator for cell mediated immunity (CMI) while WSECAg was a better stimulator for humoral immunity but generally CFECAg was better than WSECAg because the lesion was less in severity and showed good protection.