mdr1a-deficient mice lack P-glycoprotein and spontaneously develop colitis with age. Helicobacter spp. are gram-negative organisms that have been associated with colitis in certain mouse strains, but Helicobacter spp. have been excluded as contributing to the spontaneous colitis that develops in mdr1a−/− mice. We wished to determine whether infection with either H. bilis or H. hepaticus would accelerate the development of inflammatory bowel disease (IBD) in mdr1a−/− mice. We found that H. bilis infection induced diarrhea, weight loss, and IBD in mdr1a−/− mice within 6 to 17 weeks post-inoculation and before the expected onset of spontaneous IBD. Histopathology of H. bilis-induced IBD included crypt hyperplasia, inflammatory cell infiltrates, crypt abscesses, and obliteration of normal gut architecture. Reverse transcription-polymerase chain reaction and Taqman analysis from colonic tissue showed increased transcripts for interferon-γ and interleukin-10 from H. bilis-infected colitic mdr1a−/− mice. Additionally, mesenteric lymph nodes had increased cellularity with expansion of CD4⁺ and CD8⁺ T cells and B cells and increased proliferation to soluble H. bilis antigens with elaboration of interferon-γ, tumor necrosis factor-α and interleukin-10. In contrast, H. hepaticus infection of mdr1a−/− mice did not accelerate disease but rather delayed the onset of spontaneous colitis which was milder in severity. mdr1a−/− mice infected with Helicobacter spp. may provide a useful tool to explore the pathogenesis of microbial-induced IBD in a model with a presumed epithelial cell “barrier” defect.