It is well known that intravenous administration of lipopolysaccharide (LPS) induces severe toxicity in mammals. The maximum tolerated dose of intravenous administration of LPS in humans is reported to be only 1 to 4 ng/kg body weight. However, oral administration of a high dose of LPS caused no toxicity or systemic inflammation in other mammals, birds, or fish. Two weeks of oral administration of a high dose of LPS (2 mg/kg) did not induce toxicity in a rat experiment. Moreover, several experiments have reported that oral administration of LPS had preventative and curative properties against various diseases, including allergic, and lifestyle-related diseases. These results demonstrate that mucosal administration of LPS acts via a different regulatory mechanism in biological responses from that of parenteral administration. Mucosal administration of LPS is thought to be quite promising for prevention of diseases, but LPS is rarely used. In order to expand the usage of oral administration of LPS for preventing lifestyle and allergic diseases, it will be necessary to clarify the mechanisms that arouse immune responses after oral administration of LPS. This short review presents a recent observation of the usefulness of orally administered LPS.