The imbalance of Th1/Th2 subsets is an important pathogenic mechanism for insulin-dependent diabetes mellitus (IDDM). Calcitonin gene-related peptide (CGRP) has been found to play important roles in the regulation of T lymphocytes. We hypothesize that exogenous CGRP administration during insulitis may modulate the balance of Th lymphocytes, thereby providing a therapeutic intervention for IDDM. We established CGRIP gene transfer by naked plasmid injection into the skeletal muscles with electroporation enhancement. The effect of CGRP gene transfer on pathogenesis of IDDM was observed in autoimmune diabetic C57BL mice induced by multiple low-dose streptozotocin (MILDS) administration. The treatment significantly decreased morbidity of diabetes, ameliorated hyperglycemia and insulin deficiency, and inhibited lymphocyte infiltration into the islets, indicating the protection of beta cells against autoimmune destruction. CGRP gene transfer significantly inhibited T cell proliferation and secretion of the Th1 cytokine IFN-gamma, increased the level of the Th2 cytokine IL-10, but had no effect on IL-4 and TGF-beta1 secretion. CGRIP gene transfer also decreased IL-12 and IFN-gamma levels in peritoneal effusion. Our results demonstrate that CGRP gene transfer selectively suppresses the pro-inflammatory Th1 subsets and promote anti-inflammatory Th2 subsets, resulting in amelioration of beta cell destruction and reduction of IDDM occurrence in mice with MLDS-induced diabetes.