Diphtheria toxin (DT) is a single polypeptide chain of molecular weight 62,000 with two disulphide bridges. Immunization against diphtheria rests on the stimulation of antibodies against detoxified toxin which also combine with the native toxin. Because the antibodies differ functionally from each other, however, only some of them are able to neutralize toxicity. We have therefore set out to synthesize part of the amino acid sequence of the toxin whose function as a stimulator of antibodies might be less ambiguous, and have chosen the loop of 14 amino acids subtended by the disulphide bridge nearer the NH2 terminus of the molecule (Fig. 1). There is reason to think that this loop may be involved in the toxicity and immunological specificity of the molecule. We report here our finding that the tetradecapeptide (residues 188-201), when linked covalently with two different carriers, will elicit in guinea pigs antibodies which not only bind specifically with the toxin but neutralize its dermonecrotic and lethal effects. To our knowledge these results constitute the first example of successful active immunization against a lethal bacterial toxin using a synthetic antigen.