This study investigated sonic hedgehog (Shh) signalling in gastric metaplasia in the insulin-gastrin (InsGas) hypergastrinaemic mouse +/- Helicobacter felis (H. felis) infection. Sonic hedgehog gene and protein expression was reduced in pre-metaplastic lesions from non-infected mice (90% gene reduction, P<0.01) compared to normal mucosa. Sonic hedgehog was reactivated in gastric metaplasia of H. felis-infected mice (3.5-fold increase, P<0.01) compared to pre-metaplastic lesions. Additionally, the Shh target gene, glioma-associated oncogene (Gli)-1, was significantly reduced in the gastric glands of InsGas mice (75% reduction, P<0.05) and reactivated with H. felis infection (P<0.05, base of glands, P<0.01 stroma of metaplastic glands). The ability of H. felis to activate the Shh pathway was investigated by measuring the effect of target cytokine, interleukin-8 (IL-8), on Shh expression in AGS and MGLVA1 cells, which was shown to induce Shh expression at physiological concentrations. H. felis induced the expression of NF-kappaB in inflammatory infiltrates in vivo, and the expression of the IL-8 mouse homologue, protein KC, in inflammatory infiltrates and metaplastic lesions. Sonic hedgehog pathway reactivation was paralleled with an increase in proliferation of metaplastic lesions (15.75 vs 4.39% in infected vs non-infected mice, respectively, P<0.001). Furthermore, Shh overexpression increased the growth rate of the gastric cancer cell line, AGS. The antiapoptotic protein, bcl-2, was expressed in the stroma of infected mice, along with a second Shh target gene, patched-1 (P=0.0001, stroma of metaplastic gland). This study provides evidence suggesting reactivation of Shh signalling from pre-metaplastic to advanced metaplastic lesions of the stomach and outlines the importance of the Shh pathway as a potential chemoprophylactic target for gastric carcinogenesis.