Porcine edema disease (ED) is an enterotoxemia of pigs caused by Escherichia coli that produces Stx2e. In this study, the protective efficacy of a recombinant modified Stx2e toxoid was evaluated as a vaccine candidate against ED in piglets. The recombinant Stx2e toxoid was expressed and purified using a commercial E. coli expression system. A total of 25 piglets were used and divided into 5 groups (A to E), with 5 piglets in each group. All piglets (except those in group A) were intramuscularly immunized at 5 days of age (0 weeks post prime immunization; 0 WPPI) and again at 3 weeks of age (2 WPPI). Group B piglets were inoculated with sterile PBS, while groups C to E were immunized with 25 μg/piglet, 50 μg/piglet, and 100 μg/piglet of the recombinant toxoid, respectively. All piglets in groups B to E were orally challenged with virulent wild-type Stx2e⁺ F18⁺ E. coli isolates at 5 weeks of age (4 WPPI). Serum IgG titers in groups D and E were significantly increased from 2 WPPI until the end of the study. Furthermore, no clinical signs were observed in groups A and E during the 7 days following the challenge, while clinical signs of ED were observed in 80%, 60%, and 20% of piglets in groups B, C, and D, respectively. These results indicate that intramuscular vaccination with 100 μg/piglet of the recombinant modified Stx2e toxoid can provide effective protection against ED in piglets.