In gnotobiotic piglets, parenteral vaccination with formalin-killed Helicobacter pylori and oral vaccination with live bacteria induced H. pylori-specific serum immunoglobulins G, M, and A. Vaccination reduced but did not prevent infection by subsequent challenge with viable H. pylori. Oral vaccination with killed bacteria was less effective in inducing serum antibody and had no effect on bacterial colonization. Immunization status influenced the histologic response of piglets to challenge by H. pylori. Lymphoplasmacytic gastritis was more severe in parenterally vaccinated piglets than in the other groups. In addition, neutrophilic infiltrates and neutrophilic gland abscesses in the gastric mucosa were present in 5 of 7 parenterally immunized piglets, none of the orally immunized piglets, and only 1 of 8 infected nonimmune control piglets. Furthermore, there was a positive correlation between immunoglobulin G, M, and A titer at challenge and severity of both neutrophilic and lymphocytic inflammation. These results suggest that although vaccination does not prevent infection by H. pylori, infection of an immune host leads to increased severity and activity of gastritis.