Oral vaccination of large animals using PLGA MS (poly(D,L-lactide-co-glycolide)microspheres) appeared to be more challenging than immunization of mice. The purpose of this study was to deliver to GALT an immunogenic model protein (IgY), free or encapsulated by spray-drying in PLGA MS, and to evaluate systemic immune response in SPF Large White pigs. Pigs were surgically processed for local administration of IgY in three sets of experiments. In two sets of experiments, administration was locally performed in temporary ligatured intestinal segments, in jejunal Peyer's patches and in mesenteric lymph nodes. In the third experiment, pigs received IgY via an intestinal cannula. Total IgY-specific antibodies were detected in the sera of pigs after a single local immunization, but not in the sera of cannulated pigs. The study of IgG1 and IgG2 isotypes indicated that PLGA MS are able to elicit a combined serum IgG2/G1 response with a predominance of IgG1 response when locally administered. PLGA MS can be a potential oral delivery system for antigen but our results underlined the difficulty to immunize large animals like pigs. Transposition of data between small and large animals appears to be complex and suggests that physiological features need to be considered to increase intestinal availability of oral encapsulated vaccines.