Lactiplantibacillus plantarum strains are used in the food industry for their probiotic properties. Some of these bacteria have immunomodulatory effects on the host and are able to improve resistance against different pathogens, including viruses. However, to date, the bacterial genes involved in the immunomodulatory effect are not known. In this work, the complete genomes of L. plantarum MPL16, CRL1506, CRL681 and TL2766 were used to perform comparative genomics with the aim of identifying the genes involved in their differential immunomodulatory effects. L. plantarum WCFS1, a strain with proven probiotic activity, was also used for comparisons. The analysis of the genes involved in the metabolic pathways of the five strains did not reveal differences in the metabolism of amino acids, lipids, nucleotides, cofactors and vitamins, nor in the genes associated with energy metabolism or the biosynthesis of lipoproteins and teichoic acids. However, differences were found between the five strains when considering carbohydrate metabolism pathways, particularly in the presence/absence of glycosylhydrolases and glycosyltransferases. In addition, a great variability was detected in the predicted surface proteins of each L. plantarum strain. These results suggest that the surface molecules expressed in the different strains of L. plantarum could be involved in their differential ability to modulate the innate antiviral immune response.