Aims To investigate the immunoprotective ability of three Lactobacilli strains against Salmonella enterica serovar Typhimurium in a mouse model. To identify the probiotic properties involved in the protection against infection caused by this pathogen. Methods and Results The immunomodulatory effect of three different lactobacilli strains: Lactobacillus (Lact.) casei CRL 431 (probiotic bacterium), Lact.delbrueckii subsp.bulgaricus CRL 423 (Lact.bulgaricus) and Lact.acidophilus CRL 730 was compared using a mouse model of Salmonella infection. Lactobacillus casei continuous administration improved animal survival, diminished pathogen spreading outside the intestine, attenuated the intestinal inflammation, modulated cytokine profile previous and postinfection and increased the expression and secretion of IgA in the gut. Additionally, the administration of this lactobacilli increased peritoneal, Peyer's patches and spleen macrophages' phagocytic activity in healthy mice and monocyte chemotactic protein (MCP-1) released by intestinal epithelial cells in an in vitro assay. Although Lact.acidophilus increased the number of IgA-secreting cells previous and postinfection, and Lact.bulgaricus increased MCP-1 released by intestinal epithelial cells and the phagocytic activity of macrophages, these effects alone were not enough to confer protection against Salmonella Typhimurium infection in mouse. Conclusions Probiotic strain Lact.casei CRL 431 was the one that induced protection against Salmonella, by increasing the intestinal barrier function and by decreasing the local inflammatory response. Significance and Impact of the Study Salmonella spp. constitutes an important agent of foodborne diseases in the world. Not all lactobacilli, even with some immunostimulating properties at gut level, can protect against Salmonella infection. Lactobacillus casei CRL 431, a probiotic bacterium, could be useful as an oral mucosal adjuvant of the immune system to improve gut health, especially in the prevention or amelioration of Salmonella infections. We demonstrated that there is not a unique mechanism by which this protective effect was exerted.