The C57BL/6 mouse has been shown to develop gastric adenocarcinoma after Helicobacter felis infection. This model was used to determine whether mucin and trefoil factor (TFF) expression after infection was altered in a similar fashion to the changes seen in the protective gastric mucus layer of the human stomach after H. pylori infection. Our results indicate that this mouse model mimics many of the changes seen after human H. pylori infection, including increased expression of muc4 and muc5b and loss of muc5ac. These alterations in mucin expression occurred as early as 4 weeks postinfection, before the development of significant mucous metaplasia or gastric dysplasia. The decrease in muc5ac expression occurred only in the body of the stomach and was not secondary to the adaptive immune response to infection, because a similar decrease in expression was seen after infection of B6.Rag-1-/- mice, which lack B and T cells. Intriguingly, the increased expression of Muc4 and Muc5b in infected C57BL/6 mice was not seen in the infected B6.Rag-1 -/- mice. Because B6.Rag-1-/- mice do not develop gastric pathology after H. felis infection, these findings point to the potential role of Muc4 and Muc5b in disease progression. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. © The Histochemical Society, Inc.