The fruit of trifoliate orange (Poncirus trifoliate) is widely used for treating allergies including allergenic dermatitis and inflammation in oriental medicine. Increased blood IgE concentration and histamine level following dermatitis, coughing and asthma are the most important clinical symptoms of allergic diseases. Decreases in the elevated serum IgE concentrations are essential in the treatment of allergy because increased IgE blood levels are initiated in allergenic immune disorders. This study was conducted to investigate the activities of an extract of trifoliate orange fruit using 100% methanol followed by extraction with boiling water on the regulation of blood IgE concentration in the U266B1 human myeloma cell line and a 1-chloro-2,4-dinitrobenzene (DNCB) sensitized mouse model. The results revealed that the extracts of trifoliate orange suppressed IgE production in U266B1 cells in a dose dependent manner with or without lipopolysaccharide (LPS) stimulation of the cells. In addition, chemically elevated blood IgE concentrations were dramatically decreased by oral administration, ventral injection, and topical application of the trifoliate orange extracts (TOE). The results indicated that the fraction of TOE should contain an important compound of the fruit of trifoliate orange, and TOE had the ability to reduce IgE concentrations in cultured cells and a chemically sensitized in vivo mouse model.