Oral delivery of vaccines is an attractive alternative to injection. It is a non-invasive procedure which allows access to the gut-associated lymphoid tissues (GALT). Immunisation at GALT results in mucosal immune responses, which may be of particular importance in protection against infection at mucosal surfaces, as well as systemic immune responses. Vaccine antigens can be protected in the gut by encapsulation in poly(DL-lactide-co-glycolide) (PLG) microparticles. Their uptake into the immune inductive tissues of the GALT is mediated by M cells, which selectively phagocytose particles less than 10 microns in diameter. We have developed a method for the PLG encapsulation of plasmid DNA. Encapsulated DNA, expressing the insect protein luciferase under the transcriptional control of the human cytomegalovirus immediate early promoter, was administered to mice by intraperitoneal injection or oral gavage. Intraperitoneal injection of encapsulated DNA elicited good serum IgG and IgM responses and a modest IgA response. Oral administration stimulated good serum antibody titres in all three classes, and in addition, significant levels of mucosal IgA. PLG encapsulation thus has the ability to protect plasmid DNA against degradation after administration, and to facilitate its uptake into appropriate cells for the subsequent expression and presentation of antigen, in such a way as to elicit both systemic and mucosal antibody responses. This may have major implications for the design of novel vaccines and delivery strategies.