Shiga toxin 2e (Stx2e) has a pivotal role in the colonization and enterotoxicity of F18+Shiga toxin-producing Escherichia coli (STEC), which causes porcine edema disease (ED). In this study, a Stx2eA mutant, which has a Glu167Gln mutation in Stx2eA that inactivates N-glycosidase activity, was genetically engineered to evaluate its potential immunogenicity and protective efficacy. A significant increase in serum IgG1 (a Th2 indicator) was shown in mice immunized with the mutated Stx2eA. However, only 56% of the mice immunized with the toxoid (5 μg) survived following a challenge with a lethal dose 50 (LD50) of a virulent F18+STEC strain (JOL654), while mice immunized with Salmonella ghosts delivering selected antigens of F18+STEC showed an 86% survival rate. The results suggest that sole use of the mutated Stx2eA toxoid may not be an effective preventive strategy for the control of porcine ED.