The increasing clinical incidence of antibiotic resistance in bacteria is a major global health care issue. Rampant use of antimicrobials is one of the major reasons of the dramatic rise in antibiotic-resistant bacterial strains. Suitable animal models are required to improve our understanding of bacterial pathogenicity, evolution and search for novel antibiotics. The larvae of the silk moth (commonly called silkworm), Bombyx mori, have been used as an animal model for testing the pathogenicity of a clinically isolated strain of enterohemorrhagic Escherichia coli O157:H7 upon injection through hemolymph. Here, we show that a foodborne E. coli O157:H7 strain can kill silkworm larvae upon injection through either hemolymph (blood) or midgut. Bacterial number in the hemolymph started to increase after 3 h of injection into hemolymph, while the number of viable circulating hemocytes decreased. Administration of four well-known antibiotics into the larval hemolymph up to 100 mu g per larva showed therapeutic effect with varying efficacies against E. coli O157:H7 with ceftriaxone and imipenem showing better effect. Our findings indicate that silkworm larvae can be used as an animal model to screen for novel antibiotics that are effective against E. coli O157:H7.