A recently developed model for enterocolitis in mice involves pre-treatment with the antibiotic streptomycin prior to infection with Salmonella enterica serovar Typhimurium (S. Typhimurium). The contribution of Nramp1/Slc11a1 protein, a critical host defence mechanism against S. Typhimurium, to the development of inflammation in this model has not been studied. Here, we analysed the impact of Nramp1 expression on the early development of colitis using isogenic Nramp1(+/+) and Nramp1(-/-) mice. We hypothesized that Nramp1 acts by rapidly inducing an inflammatory response in the gut mucosa creating an antibacterial environment and limiting spread of S. Typhimurium to systemic sites. We observed that Nramp1(+/+) mice showed lower numbers of S. Typhimurium in the caecum compared with Nramp1(-/-) mice at all times analysed. Acute inflammation was much more pronounced in Nramp1(+/+) mice 1 day after infection. The effect of Nramp1 on development of colitis was characterized by higher secretion of the pro-inflammatory cytokines IFN-gamma, TNF-alpha and MIP-1alpha and a massive infiltration of neutrophils and macrophages, compared with Nramp1(-/-) animals. These data show that an early and rapid inflammatory response results in protection against pathological effects of S. Typhimurium infection in Nramp1(+/+) mice.