Helicobacter pylori produces a cytotoxin that was initially detected as the ability of broth culture filtrates of this bacterium to induce intracellular vacuolation of cultured cells. Fifty-three percent of more than 200 isolates of H. pylori tested produce the cytotoxin, which appears to be unique to H. pylori. Results of characterization studies suggest that the cytotoxin is a high-molecular-weight protein. Detection of serum antibody to the cytotoxin by neutralization or immunoblotting indicates that this toxin is produced in vivo. The cytotoxin is more frequently associated with cases of peptic ulceration than with cases of gastritis; this finding suggests that the toxin contributes to the severity of disease associated with H. pylori infection.