Modified Escherichia coli heat-stable enterotoxin (STa) peptides have been synthesized to identify structures that retain the immunological properties of native STa but lack toxicity. Two synthetic peptides, corresponding to the 15 C-terminal amino acid residues of STa (STh) except for the replacement of one or two Cys residues by Ala, had ≥ 35 000-fold reduced toxicity in infant mice despite almost intact activity as compared to native STa to inhibit monoclonal anti-ST antibody binding to solid phase STa. Three shorter peptides of 6–8 amino acid residues also did not manifest any toxic activity and showed significant but much reduced reactivity with anti-STa antibodies.