Progression of acute myocarditis involves a variety of inflammatory events. Mast cells have been implicated as the source of various cytokines, chemokines and histamine in acute inflammation and fibrosis. Interleukin (IL)-10 has well-known immunomodulatory actions that are exerted during the recovery phase of myocarditis. In this study, 9-week-old male Lewis rats were immunized with cardiac myosin. A plasmid vector expressing mouse IL-10 cDNA (800 mug per rat) was then transferred three times (7, 12 and 17 days after immunization) into the tibialis anterior muscles of the rats by electroporation. Microscopic examination of mast cells was carried out on toluidine blue-stained transverse sections of the mid ventricles. Mouse IL-10 gene transfer significantly reduced mast cell density, cardiac histamine concentration and mast cell growth, and prevented mast cell degranulation. Furthermore, improvement in both myocardial function and the overall condition of the rats was evident from the reduction in the heart weight-to-body weight ratio and inflammatory infiltration as well as improvement in hemodynamic and echocardiographic parameters. These findings suggest that IL-10 gene transfer by electroporation protected against myocarditis via mast cell inhibition.